Compositions and Methods for Treating Cancer

ABSTRACT

A double stranded RNA interference (RNAi) agent comprising at least one of (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA comprises a sense strand and an antisense strand forming a duplex, (ii) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, or (iii) a cocktail of (i) and (ii) and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA and the use of the RNAi agent as a pharmaceutical composition for the treatment of cancer in subjects in need of treatment.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-In-Part application of International Patent Application No. PCT/US2019/068423, filed on Dec. 23, 2019, titled “Compositions and Methods for Treating Cancer”, which claim priority to and the benefit of U.S. Provisional Patent Application No. 62/785,592, titled “Compositions and Methods for Treating Cancer”, filed on Dec. 27, 2018. This application also claims priority to and the benefit of the filing of U.S. Provisional Patent Application No. 63/044,771, filed on Jun. 26, 2020, titled “Compositions and Methods for Treating Cancer”. The specification and claims thereof are incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 24, 2021, is named 32064-1035_CIP_SL.txt and is 446,136 bytes in size.

BACKGROUND

A variety of cancer therapies and treatments exist such as surgical resection of solid tumors, radiation, and chemotherapy. While surgical resection and radiation are used on localized tumors, chemotherapy is often delivered systemically and impacts both cancer and non-cancer cells, leading to severe and even life-threatening side effects. Older cancer drugs, including alkylators, nucleotide antimetabolites, and tubulin poisons, cause significant side effects because they are similarly toxic to normal cells as to cancer cells, especially those normal cells undergoing routine cell division in the intestine, scalp, and skin. For this reason, much of the effort in contemporary cancer drug discovery is devoted to finding targeted therapeutics which differentiate between cancer cells and normal cells (Neidle et al., (2014) Cancer Drug Design and Discovery). This has led to drugs which inhibit the function of oncolytic proteins that are mutated, overexpressed, or abnormally hyperactive in cancer but not in normal cells. Examples of such drugs include kinase inhibitors, histone deacetylase inhibitors, proteasome inhibitors, mTOR inhibitors, BCL2 inhibitors, and isocitrate dehydrogenase inhibitors. Significant effort has also been devoted to targeting cell surface antigens which are differentially expressed in cancer cells compared to normal cells. Monoclonal antibodies and antibody-drug conjugates targeting cancer cell surface antigens have thus been developed as cancer therapeutics (Beck et al., (2017) Nat Rev Drug Disc 16, 315-337). Another point of differentiation between cancer cells and normal cells is metabolism. It was discovered many years ago that many cancer cells utilize glucose fermentation to generate ATP as opposed to the process of oxidative phosphorylation used by normal cells. A drug targeting isocitrate dehydrogenase, involved in abnormal glucose metabolism in cancer cells, was recently approved by the FDA (Dhillon (2018) Drugs 78, 1509-1516). Abnormalities in one-carbon metabolism, which encompasses the folate and methionine cycles and affects nucleotide synthesis and DNA methylation as a way of controlling gene expression, are strongly associated with some cancers (Fanidi et al., (2019) Int J Cancer 145, 1499-1503; Yang (2018) Front Oncol 8, 493). In this connection, it has been known for a long time that certain synthetic analogs of folic acid (antifolates) can inhibit the growth of cancer cells. It is also known that some cancer cells are dependent for survival on the amino acid methionine. If methionine is restricted, the cancer cells die, while this has little effect on normal cells. In recent years, evidence has begun to emerge that some cancer cells might have an abnormal dependency on vitamin B12. The nature of this dependency is not understood but might, in part, involve the use of vitamin B12 as a catalytic cofactor by the enzyme methionine synthase in one-carbon metabolism.

Vitamin B12 (cobalamin) is an essential micronutrient in the human diet. It is a cofactor for the metabolic enzymes methionine synthase and methylmalonyl-CoA mutase (Fedosov et al., (2012) Water Soluble Vitamins (book) 56, 347-367). After oral ingestion and transport through the intestine, cobalamin is almost completely protein bound in plasma to the chaperone proteins transcobalamin 1 (TCN1, haptocorrin, R-binder) (TCO1_HUMAN) and transcobalamin 2 (TCN2) (TCO2_HUMAN). The TCN2-cobalamin complex (TCN2-Cbl) is taken up by most cells using the process of receptor-mediated endocytosis and has a plasma half-life of 1-15 h. TCN2 has a high affinity and specificity for cobalamin in its various dietary and nutritional supplement forms, such as methyl cobalamin, adenosyl cobalamin and cyanocobalamin (Fedosov et al., (2007) Biochem 46, 6446-6458). TCN1 is a glycoprotein that exists in two different forms in plasma (Marzolo and Farfan (2011) Biol Res 44, 81-105). The most abundant form is sialylated and has a plasma half-life of about 10 days (Bor (2004) Clin Chem 50, 1043-1049). A less abundant form is desialylated and has a plasma half-life of a few minutes. Unlike TCN2-Cbl, which can be taken up by almost all cell types, the transcobalamin 1-cobalamin complex (TCN1-Cbl) is quickly taken up by certain liver cells, only in its desialylated form, by receptor-mediated endocytosis.

CD320 and LRP2 are two receptors involved in the uptake of cobalamin as TCN2-Cbl. CD320, a member of the low-density lipoprotein receptor (LDLR) family, is constitutively expressed in most cells and is the receptor primarily responsible for the uptake of cobalamin (Quadros (2013) Biochimie 95, 1008-1018). CD320 is overexpressed in some types of cancer (Sycel et al., (2013) Anticancer Res 33, 4203-4212; Amagasaki (1990) Blood 76, 1380-1386). There is also evidence that CD320 facilitates the transport of TCN2-Cbl through the blood-brain barrier into the brain (Lai et al.; (2013) FASEB 27, 2468-2475). LRP2 is another receptor in the LDLR family. It is expressed most highly in the kidney but also in other tissues. In addition to cobalamin, LRP2 also transports sundry proteins and small molecules, including albumin, insulin and vitamin D (Mazolo et al., (2011) Biol Res 44, 89-105). In the liver, the asialoglycoprotein receptor (ASGR) uptakes TCN1-Cbl by receptor-mediated endocytosis so long as TCN1 is in its desialylated form. Normal liver cells and liver cancer cells express very high levels of ASGR (50,000 receptors per cell), making this receptor attractive as a portal for delivering drugs to the liver (Luo et al., (2017) Biomedicine and Pharmacotherapy 88, 87-94; Stockert (1995) Physiological Rev 75, 595-609; Soda et al., Blood (1985) 65, 795-802).

After receptor mediated endocytosis, cobalamin is sequestered in the endosome, where the endosomal membrane prevents passive egress to the cytosol. A specialized protein (cblF) facilitates the transport of cobalamin through the endosomal membrane to the cytosol (Banerjee et al., (2009) Curr Opin Chem Bio 13, 484-491).

BRIEF SUMMARY OF THE INVENTION

One embodiment of the present invention provides for a double stranded RNA interference (RNAi) agent comprising at least one of (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA comprises a sense strand and an antisense strand forming a duplex, (ii) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, or (iii) a cocktail of (i) and (ii) and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA. For example, the antisense strand of (i) the first dsRNA includes a region of complementarity to a CD320 RNA transcript and for example the sense strand of (i) the first dsRNA is selected from Table 5. The antisense strand of (ii) the second dsRNA includes a region of complementarity to an LRP2 RNA transcript and the sense strand of (ii) the second dsRNA are selected from Table 6. In one example, (i) the first dsRNA or (ii) the second dsRNA comprises a duplex region which is 16-30 nucleotide pairs in length. In another example, (i) the first dsRNA or (ii) the second dsRNA comprises a duplex region which is 21-23 nucleotide pairs in length. In one embodiment, the double stranded RNAi agent includes at least one strand of: (i) the first dsRNA or (ii) the second dsRNA which comprises a 3′ overhang of at least 2 nucleotides. Further still, in one embodiment, the antisense strand of (i) the first dsRNA, comprises the nucleotide sequence selected from (5′→3′):

(SEQ ID NO: 17) CAGUUGCGCAGUUUCUUGUCAGUUCdTdT; (SEQ ID NO 18) CAGUUGCGCAGUUUCUUGUCAGUUCdT*dT; (SEQ ID NO 19) mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmU mGmUmCmAmGmUmUmCdT*dT; (SEQ ID NO 21) mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmU mGmUmCmAmGmUmUmC; (SEQ ID NO 23) CmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmUm GmUmCmAmGmUmUmCdT*dT; (SEQ ID NO 24) mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2f UmC2fUmU2fGmU2fCmA2fGmU2fUmCdT*dT; (SEQ ID NO 25) mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2f UmC2fUmU2fGmU2fCmA2fGmU2fUmC; (SEQ ID NO 28) 2fCmA2fGmU2fUmG2fCmG2fCmA2fGmU2fUm U2fCmU2fUmG2fUmC2fAmG2fUmU2fCdT*dT; (SEQ ID NO 29) 2fCmA2fGmU2fUmG2fCmG2fCmA2fGmU2fUm U2fCmU2fUmG2fUmC2fAmG2fUmU2fC; (SEQ ID NO 30) mC2fA2fG2fU2fU2fG2fC2fG2fC2fA2fG2fU 2fU2fU2fC2fU2fU2fG2fU2fC2fA2fG2fU2 fU2fCdT*dT; (SEQ ID NO 32) mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2f UmC2fUmU2fGmU2fCmA2fGmU2fUmCdT*dT; (SEQ ID NO 33) mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2f UmC2fUmU2fGmU2fCmA2fGmU; (SEQ ID NO 34) mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2f UmC2fU2fU2fG2fU2fC2fA2fG2fU); wherein, mA, mC, mG, and mU are 2′-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2′-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

Further still, in another embodiment, the double stranded RNAi agent includes the antisense strand of (i) the first dsRNA, that comprises the nucleotide sequence selected from (5′→3′)

(SEQ ID NO 64) AAGAGCUCAGGUCUCUGAGGGdTdT; (SEQ ID NO 65) AAGAGCUCAGGUCUCUGAGGGdT*dT; (SEQ ID NO 66) mAmAmGmAmGmCmUmCmAmGmGmUmCmUmCmUmGmAmGm GmGdT*dT; (SEQ ID NO 68) mAmAmGmAmGmCmUmCmAmGmGmUmCmUmCmUmGmAmGm GmG; (SEQ ID NO 71) mA2fAmG2fAmG2fCmU2fCmA2fGmG2fUmC2fUmC2f UmG2fAmG2fGmGdT*dT; (SEQ ID NO 72) mA2fAmG2fAmG2fCmU2fCmA2fGmG2fUmC2fUmC2f UmG2fAmG2fGmG; (SEQ ID NO 75) 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCm U2fGmA2fGmG2fGdT*dT; (SEQ ID NO 76) 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCm U2fGmA2fGmG2fG; (SEQ ID NO 77) mA2fA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCm U2fGmA2fGmG2fG; (SEQ ID NO 78) mA2fA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCm U2fGmA2fGmG2fGdT*dT; (SEQ ID NO 79) 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCm U2fGmA2fGmG2fGdT*dT; (SEQ ID NO 81) 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fC2 fU2fG2fA2fG2fG2fG; wherein, mA, mC, mG, and mU are 2′-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2′-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

In another embodiment the double stranded RNAi agent of (ii) the second dsRNA comprises the nucleotide sequence selected from (5′→3′)

(SEQ ID NO: 417) UUUGAUAGCACCAAACCUAGAGCCCdTdT; (SEQ ID NO: 418) UUUGAUAGCACCAAACCUAGAGCCCdT*dT; (SEQ ID NO: 419) mUm[mUmGmAmUmAmGmCmAmCmCmAmAmAmCmCmUmAmGmAmGmCmCm CdT*dT; (SEQ ID NO: 421) mUmUmUmGmAmUmAmGmCmAmCmCmAmAmAmCmCmUmAmGmAmGmCmCm C; (SEQ ID NO: 424) mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2f GmA2fGmC2fCmCdT*dT]; (SEQ ID NO: 425) mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2f GmA2fGmC2fCmC; (SEQ ID NO: 429) mU2fAmU2fCmA2fAmA2fCmC2fUmC2fGmA2fUmA2fGmC2fAmA2f CmA2fCmC2fGmC; (SEQ ID NO: 430) mU2fU2fU2fG2fA2fU2fA2fG2fC2fA2fC2fC2fA2fA2fA2fC2f C2fU2fA2fG2fA2fG2fC2fC2fCdT*dT; (SEQ ID NO: 432) mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2f GmA2fGmC2fCmCdT*dT; (SEQ ID NO: 433) mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2f GmA2fGmC; and (SEQ ID NO: 434) mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fC2fC2fU2fA 2fG2fA2fG2fC wherein, mA, mC, mG, and mU are 2′-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2′-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

In a further embodiment, the double stranded RNAi agent antisense strand of (ii) the second dsRNA comprises the nucleotide sequence selected from (5′→3′)

(SEQ ID NO: 448) UUUGCAAUGACUCUCCUAUCAGUCCdTdT (SEQ ID NO: 449) UUUGCAAUGACUCUCCUAUCAGUCCdT*dT; (SEQ ID NO: 450) mUmUmUmGmCmAmAmUmGmAmCmUmCmUmCmCmUmAmUmCmAmGmUmCm CdT*dT; (SEQ ID NO: 452) mUmUmUmGmCmAmAmUmGmAmCmUmCmUmCmCmUmAmUmCmAmGmUmCm C; (SEQ ID NO: 455) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2f CmA2fGmU2fCmCdT*dT; (SEQ ID NO: 456) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2f CmA2fGmU2fCmC; (SEQ ID NO: 458) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2f CmA2fCmU2fCmC; (SEQ ID NO: 459) 2fUmU2fUmG2fCmA2fAmU2fGmA2fCmU2fCmU2fCmC2fUmA2fUm C2fAmG2fUmC2fCdT*dT; (SEQ ID NO: 460) mU2fAmU2fCmC2fUmA2fAmG2fUmC2fAmC2fAmC2fGmU2fUmU2f GmA2fCmU2fGmC; (SEQ ID NO: 461) mU2fU2fU2fG2fC2fA2fA2fU2fG2fA2fC2fU2fC2fU2fC2fC2f U2fA2fU2fC2fA2fG2fU2fC2fCdT*dT; (SEQ ID NO: 463) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2f CmA2fGmU2fCmCdT*dT; (SEQ ID NO: 464) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2f CmA2fGmU; (SEQ ID NO: 465) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fC2fU2fA2fU 2fC2fA2fG2fU wherein, mA, mC, mG, and mU are 2′-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2′-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

For example, when the RNAi agent comprises (iii) the combination of (i) the first dsRNA and (ii) the second dsRNA, the antisense strand of (i) the first dsRNA is selected from

(SEQ ID NO: 17) CAGUUGCGCAGUUUCUUGUCAGUUCdTdT; (SEQ ID NO 18) CAGUUGCGCAGUUUCUUGUCAGUUCdT*dT; (SEQ ID NO 64) AAGAGCUCAGGUCUCUGAGGGdTdT; and (SEQ ID NO 65) AAGAGCUCAGGUCUCUGAGGGdT*dT;  and the antisense strand of (ii) the second dsRNA is selected from (SEQ ID NO: 417) UUUGAUAGCACCAAACCUAGAGCCCdTdT; (SEQ ID NO: 418) UUUGAUAGCACCAAACCUAGAGCCCdT*dT; (SEQ ID NO: 448) UUUGCAAUGACUCUCCUAUCAGUCCdTdT; and (SEQ ID NO: 449) UUUGCAAUGACUCUCCUAUCAGUCCdT*dT; wherein * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.

In one embodiment, (i) the first dsRNA has the duplex structure of (SEQ ID NOs: 17 and 110) or (SEQ ID NOs: 18 and 111). In another (ii) the second dsRNA has the duplex structure of (SEQ ID NOs: 417 and 808) or (SEQ ID NOs: 448 and 822).

Another embodiment provides for an isolated cell comprising a double stranded RNAi gent of (i), (ii) or (iii).

For example, the sense strand of (i) the first dsRNA is no more than 30 nucleotides in length, and the antisense strand of (i) the first dsRNA is no more than 30 nucleotides in length. For example, the sense strand of (ii) the second dsRNA is no more than 30 nucleotides in length, and the antisense strand is no more than 30 nucleotides in length.

Yet another embodiment provides a pharmaceutical composition for inhibiting expression of a CD320 gene, the pharmaceutical composition comprising a double stranded RNAi agent (i) or (iii). Further the pharmaceutical composition may include an excipient.

Yet another embodiment provides a pharmaceutical composition for inhibiting expression of an LRP2 gene, the composition comprising a double stranded RNAi agent (ii) or (iii). Further the pharmaceutical composition may include an excipient.

Another embodiment of the present invention provides a method for inhibiting proliferation of a cancer cell (CC) comprising contacting of the CC with an inhibitor of CD320 add/or LRP2 in an amount effective to inhibit proliferation of the CC. For example, the CC may express CD320 and/or LRP2 or both.

Another embodiment of the present invention provides a method for treating a therapeutically-resistant cancer in a subject who has previously received a therapy, comprising administering to the subject an inhibitor of CD320 add/or LRP2 in an amount effective to inhibit or kill cancer cells (CCs) present in the therapeutically-resistant cancer.

Another embodiment of the present invention provides a method for treating cancer in a subject who has recurring or relapsed cancer comprising administering to a subject an inhibitor of CD320 add/or LRP2 in an amount effective to inhibit or kill CCs in the cancer.

The CC is from a cancer selected from melanoma, glioblastoma, lung carcinoma, breast carcinoma, triple negative breast carcinoma, hepatocellular carcinoma, renal carcinoma, pancreatic carcinoma, ovarian carcinoma and prostate carcinoma.

The CD320 inhibitor is selected from an antibody that binds CD320, a small molecule inhibitor of CD320, and a RNAi agent that hybridizes to a nucleic acid sequence encoding CD320.

Further, the method of inhibiting proliferation of a CC, treating a therapeutically resistive cancer in a subject or has a recurring or relapsed cancer comprises administering a cancer therapeutic in combination with an RNAi agent that hybridizes to an mRNA encoding for CD320 or an RNAi agent that hybridizes to an mRNA encoding for LRP2. For example, the cancer therapeutic is selected from the antifolate class, epigenetic modulatory class, or a small molecule or protein inhibitor of CD320 function or LRP2 function, such as an antibody for CD320 or an antibody for LRP2. Further still, the method further comprises administering metformin. For example, the RNAi agent comprises an antisense strand of Table 5 or of Table 6.

The inhibitor is selected from the group consisting of an antibody that binds LRP2, a small molecule inhibitor of LRP2, and an RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2. For example, the method further comprises administering a cancer therapeutic selected from the antifolate class, epigenetic modulatory class, or the small molecule or protein inhibitor of LRP2 function, such as an antibody, in combination with an RNAi agent that hybridizes to an mRNA encoding for LRP2.

The method further comprises administering a cancer therapeutic in combination with an RNAi agent that hybridizes to an mRNA encoding for LRP2.

One embodiment of the present invention provides for a method for inhibiting proliferation of a cancer cell (CC) comprising contacting of a CC with a composition comprising an inhibitor of CD320 and an inhibitor of LRP2 in an amount effective to inhibit proliferation of the CC. For example, the composition is a cocktail comprising i) the CD320 inhibitor selected from an antibody that binds CD320, a small molecule inhibitor of CD320, and a RNAi agent that hybridizes to a nucleic acid encoding CD320 and any combination thereof, and the LRP2 inhibitor selected from an antibody that binds LRP2, a small molecule inhibitor of LRP2, and a RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2 and any combination thereof. Further, the method further comprises administering a cancer therapeutic selected from the antifolate class and epigenetic modulatory class. For example, the RNAi agent that hybridizes to the mRNA encoding for CD320 comprises a first double-stranded ribonucleic acid (dsRNA) for inhibiting expression of CD320, wherein the first dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a CD320 RNA transcript and the RNAi agent that hybridizes to the mRNA encoding for LRP2 comprises a second dsRNA for inhibiting expression of LRP2, wherein the second dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an LRP2 RNA transcript. In a further example, the antisense strand that is complementary to CD320 RNA transcript is selected from Table 5 and the antisense strand that is complementary to the RNA transcript for LRP2 is selected from Table 6. The method further comprises administering a cancer therapeutic selected from the antifolate class and epigenetic modulatory class. The method further comprises administering a cancer therapeutic selected from the immunomodulatory class. Further still, the method further comprises administering metformin.

One aspect of one embodiment of the present invention provides a method for the inhibition of CD320 and LRP2 protein expression, such that the levels of these proteins are reduced in treated cells compared to their endogenous levels in untreated cells; this inhibition may also be referred to as the knockdown of CD320 and LRP2 expression. The method entails the use of a cocktail of small interfering RNA molecules, otherwise known as siRNAs, which guide the mRNA sequences encoding for either CD320 or LRP2 into an enzymatic complex which leads to targeted destruction of these mRNAs.

Another aspect of the present invention provides a method for the individual or concurrent inhibition of LRP2 and CD320 protein expression, which inhibits the growth of many cancer cells as compared to non-cancer (normal) cells. In some instances, CD320 or LRP2 protein knockdown alone is sufficient to severely inhibit cancer cell proliferation compared to normal cells.

Another aspect of the present invention provides for inhibition of cancer cell proliferation by inhibiting LRP2 receptor expression.

Mechanistic investigations into the selectivity of porphyrin uptake by cancer cells led to several nonobvious compounds and methods of using the compound(s). It was discovered that the knockdown of the expression of either CD320 gene or LRP2 gene or the simultaneous knockdown of the expression of CD320 gene and LRP2 gene caused cell death or inhibition of cell growth in a panel of lung cancer cell lines, compared to normal fibroblasts. The experimental outline is illustrated in FIG. 1 . In these experiments, cells were plated on day 0. The next day (day 1), virus particles encoding short hairpin RNAs (shRNAs) directed to the CD320 gene and the LRP2 gene or an irrelevant shRNA control were added to the cell culture together with protamine sulfate, a reagent that facilitates cell entry of the virus particles.

Further investigations revealed that knockdown of the expression of either the CD320 gene or LRP2 gene or the simultaneous knockdown of the expression of CD320 and LRP2 genes using small interfering RNAs (siRNAs) caused cell death or inhibition of cell growth in a panel of cancer cell lines that included lung cancer, prostate cancer, breast cancer, glioblastoma and melanoma, compared to normal fibroblasts (FIG. 9-10 ). It was also found that that knockdown of one gene, either CD320 or LRP2, led to increased expression of the other in some cancer cell lines.

One aspect of the present invention provides for the knockdown of the CD320 receptor, the LRP2 receptor or the simultaneous knockdown of both in vivo and in vitro cancer cells that express CD320 mRNA and/or LRP2 mRNA.

Another aspect of the present invention is a method to inhibit cell growth or cause cell death of cancer cells treated with a compound as described herein, while leaving normal cells unaffected or inhibiting cell growth to a lesser degree or producing less cell death as compared to a cancer cell treated with the same amount of the compound.

Another aspect of a first compound and method of use is a selective therapy which inhibits proliferation of cancer cells and/or kills cancer cells with an inhibition of LRP2 Receptor while leaving normal cells unharmed.

Another aspect of a second compound and method of use is a selective therapy which inhibits proliferation of cancer cells and/or kills cancer cells with an inhibition of CD320 Receptor while leaving normal cells unharmed.

Another aspect of the present invention provides for treating a cancer by administering a therapy to selectively inhibit proliferation of a cancer cell(s) and/or kill a cancer cell(s) with one or more of the following, a first compound that is an inhibitor of CD320 receptor, a second compound that is an inhibitor of LRP2 receptor or a combination thereof.

DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The accompanying drawings, which are incorporated into and form a part of the specification, illustrate one or more embodiments of the present invention and, together with the description, serve to explain the principles of the invention. The drawings are only for the purpose of illustrating one or more embodiments of the invention and are not to be construed as limiting the invention. In the drawings:

FIG. 1 illustrates an experimental design for knocking down CD320 and LRP2 in a cell. Cells were plated on day 0. The next day (day 1), virus particles encoding short hairpin RNAs (shRNAs) directed at the CD320 and LRP2 mRNA or a non-targeting shRNA control were added to the cell culture together with protamine sulfate, a reagent that facilitates cell entry of the virus particles. Table 1 shows the sequences that were used. Each shRNA coding sequence was also combined with a unique drug resistance gene, which would allow for selecting those cells that had taken up the shRNA; cells that had not taken up the shRNA would not survive. On day 2, drug selection was started. On day 3, the cells were harvested and plated in a new dish. Only the cells with a drug resistance gene, i.e., those cells that had taken up shRNA virus particles would survive this re-plating procedure. From day 4 on, each culture was closely observed for cell growth. Cells infected with the non-targeting negative control shRNA continued growing—data not shown. The results for the cell lines that expressed the CD320+LRP2 shRNAs are shown in Table 1.

FIGS. 2 A-C illustrates sensitivity of cancer cell lines to knockdown of CD320 and LRP2. Normal cells (GM05659 fibroblasts) or cancer cells were infected with lentiviruses expressing shRNAs to control sequences or to shCD320 and shLRP2 as described in FIG. 1 . The cells were grown as described in FIG. 1 . On the ninth day after transfection with the lentiviruses, pictures of the cells were taken. The solid oval indicates healthy growth of normal fibroblast infected with shRNAs to CD320 and LRP2. The broken line ovals indicate unhealthy dying cancer cells infected with shRNAs targeting CD320 and LRP2 (FIG. 2A). The fields of cells in FIG. 2A were counted and quantified and illustrated in FIG. 2B. The data in FIG. 2B were normalized to the number of control cells and illustrated in FIG. 2C. FIG. 2C. shows that the cultures of cells infected with lentivirus encoding the shRNAs against CD320 and LRP2 (white bars) contain far fewer cells than the cultures of cells exposed to the shRNA control (black bar).

FIGS. 3 A-F illustrate graphs of protein levels resulting from transfection of HEK293, MDA-MB-435S and MDA-MB-231 cells with siRNA to LRP2 and CD320. HEK293, MDA-MB-435S and MDA-MB-231 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated OSC17 and OSC47. siRNAs targeting LRP2 are designated OSL245, OSL47, OSL104, OSL90 and OSL119. Whole cell lysates were prepared and immunoblotted for CD320 and LRP2 protein levels. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA transfection. The graphs FIGS. 3 A-F represent the fold change of protein levels compared to siScramble (OSS1 or OSS2). (Average +/− SEM is shown, n=3).

FIGS. 4 A-F illustrate a graph of cells after transfection of LnCAP, MCF-7 and U251 cells with siRNA to LRP2 and CD320. LnCAP, MCF-7 and U251 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated OSC17 and OSC47. siRNAs targeting LRP2 are designated OSL245, OSL47, OSL104, OSL90 and OSL119). Whole cell lysates were prepared and immunoblotted for CD320 and LRP2 protein levels. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA transfection. The graphs FIGS. 4 A-F represent the fold change of protein levels compared to siScramble (OSS2).

FIG. 5A-C illustrate graphs of protein levels after transfection of A172, DU145 and GM05659 cells with siRNA to LRP2 and CD320. A172, DU145 and GM05659 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated OSC17 and OSC47. siRNAs targeting LRP2 are designated OSL245, OSL47, OSL104, OSL90 and OSL119). Whole cell lysates were prepared and immunoblotted for CD320. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA transfection. The graphs FIG. 5A-C represent the fold change of protein levels compared to siScramble (OSS2).

FIG. 6 illustrates a graph of relative LRP2 protein expression in various cell lines—Lysates were made from the cell lines indicated on the x-axis, and western blot was performed to determine LRP2 protein levels. The results represent the averages +/−SEM of three independent lysates.

FIGS. 7 A-B illustrates graphs of the effect of doxorubicin treatment on cell viability, as measured by the CTG assay. A172 and HCC15 cells were plated at 1200 cells/well in a 96 well plate. The next day, cells were treated with doxorubicin at the indicated concentrations. Four days after doxorubicin treatment was initiated, the cells were assayed for viability using the CTG assay. The dashed line indicates the non-linear fitting of the data to calculate an IC₅₀ value.

FIG. 8 is a schematic overview of the functional assay for screening siRNA effects on cell proliferation to facilitate quantification of the effects of knocking down CD320 and LRP2 on cell proliferation. Cells were plated in a 24-well plate. The next day, the cells were transfected with siRNAs targeting CD320 (OSC17, OSC47) and/or targeting LRP2 (05L231, OSL245), or a control siRNA (OSS2). The cell lines may require repeated transfections and/or time for efficient toxicity (cell line dependent). In this experimental set-up there is room for repeat infection should some cell lines require that for efficient toxicity. In addition, in a small subset of the wells, cells were only treated with doxorubicin as a positive control for toxicity. At the end of the study, the cell lines are analyzed for cell growth by the CTG assay.

FIGS. 9 A-E illustrate graphs of the percent cell survival of siCD320 and siLRP2 on cell proliferation—Cell lines representative of several types of cancers (lung, brain) or normal fibroblasts were transfected with individual or combinations of siRNAs targeting CD320 (OSC17, OSC47) or LRP2 (05L231, OSL245), individually at 20 nM or in combination (10 nM each), or a negative control siRNA (OSS2) (20 nM) as indicated. Cells were repeatedly transfected as outlined in Table 9 for efficient toxicity, then assayed for viability by the CTG assay. Doxorubicin-treated cells served as a positive control for cell toxicity in our assays (Table 8).

FIGS. 10 A-E illustrate graphs of the effects of siCD320 and siLRP2 on cell proliferation—Cell lines representative of several types of cancers (breast, prostate, skin) were transfected with individual or combinations of siRNAs targeting CD320 (OSC17, OSC47) or LRP2 (05L231, OSL245) as indicated. Cells were repeatedly transfected as outlined in Table 9 for efficient toxicity, then assayed for viability by the CTG assay. Doxorubicin-treated cells served as a positive control for cell toxicity in our assays (Table 8).

FIGS. 11A-B illustrate the effects of siCD320 and siLRP2 molar proportions on cell proliferation with different molar proportions of siRNA targeting CD320 and siRNA targeting LRP2. Cell lines representative of two types of cancers (breast, prostate) were transfected with different proportions of siRNAs targeting CD320 (OSC17) or LRP2 (05L245) (0-20 nM) or a negative control siRNA (OSS2) as indicated. Cells were repeatedly transfected for efficient toxicity then assayed for viability by the CTG assay. Doxorubicin-treated cells served as a positive control for cell toxicity in our assays (Table 8).

FIGS. 12A-B illustrate graphs of the duration of the knockdown effect for siCD320 and siLRP2 on MDA-MD-231 cells. A representative breast cancer cell line (MDA-MD-231) was transfected on Day 0 with 20 nM of an siRNA targeting CD320 (OSC17) or an siRNA targeting LRP2 (05L245) or a negative control siRNA (OSS2) and the percentage of protein knockdown was analyzed daily over a period of five days by western blot. Protein levels were normalized to the negative control (OSS2).

FIG. 13 is a schematic of polyethylinimine (PEI) and siRNA complexation. PEI and siRNAs are mixed together. Subsequently, polyplexes (a nanoparticle, broadly speaking) of the PEI-siRNA complex form, which are able to enter the cell.

FIG. 14 is a schematic that illustrates that siRNAs are short RNA duplexes of generally 16 to 30 nucleotides; the guide sequence of the siRNA is complementary to a mRNA expressed in the cell. Exogenous siRNA duplexes are introduced into the cell via a method of transfection. The siRNA duplexes are separated via the RISC/AGO (RNA-induced silencing complex) complex, whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC/AGO complex, which has RNAse activity, resulting in mRNA degradation, and the protein encoded by the mRNA is not produced. This causes the “knockdown” effect or reduced protein levels of the gene targeted by the siRNA compared to control treated cells.

FIGS. 15 A-B illustrate graphs of A172 cell line or MDA-MD-435S cell lines treated with control siRNA (OSS1, OSS2) and siRNA directed to CD320 mRNA (OSC17, OSC47) and siRNA directed to LRP2 mRNA (05L231, OSL245) to determine the effectiveness of INTERFERin, a polyethanolamine transfection reagent, in delivering siRNAs to cancer cells.

FIGS. 16 A-D illustrate plated cells showing the effects of siCD320 and siLRP2 on four cell lines. Cell lines representative of four types of cancers (breast, two prostate, skin) were transfected with siRNAs targeting CD320 (OSC17) or LRP2 (05L245) individually at 20 nM or in combination (10 nM each) or a negative control siRNA (OSS2) (20 nM) as indicated. Cells were repeatedly transfected for efficient toxicity as in Table 9 and then analyzed by microscopy as indicated.

FIG. 17 illustrates a graphical depiction of CD320 mRNA. UTR references the untranslated region, and the CDS references the protein coding sequence.

FIG. 18 illustrates a graphical depiction of LRP2 mRNA UTR references the untranslated region, and the CDS references the protein coding sequence.

FIGS. 19A-G illustrates the structures for unnatural nucleotides which may be incorporated within the sequence of an RNAi. “B” represents a natural (G, C, A, U) RNA nucleobase, a DNA nucleobase, or an unnatural nucleobase. FIG. 19A shows certain chemical modifications to the ribose 2′-position and phosphate moieties. FIGS. 19B-D shows skeletal modifications to the ribose moiety that comprise bridging groups. FIG. 19E shows a deletion of the C2′-C3′ bond. FIGS. 19F-G shows other skeletal modifications to the ribose moiety wherein a six-membered ring replaces the five-membered ring.

FIG. 20 illustrates a schematic for the in vivo murine xenograft model for breast cancer. MDA-MB-231 cells were implanted into the flank of NSG mice and grown to a volume of 70 mm³ after which siRNAs targeting CD320 (OSC17) and LRP2 (05L245) were injected intratumorally once every fourth day.

DETAILED DESCRIPTION OF THE INVENTION

One or more embodiment of the present invention provides methods and RNAi compounds for modulating the expression of a CD320 gene and/or an LRP2 gene in a cell. In certain embodiments, expression of a CD320 gene and/or a LRP2 gene is reduced or inhibited using an CD320 and/or LRP2 specific RNAi. Such inhibition can be useful in treating disorders such as cancer and/or creating cell lines that are useful for screening drugs that treat cancer

The present invention also relates to a method for knocking down (partially or completely) the targeted genes.

One embodiment of the method of producing knockdown cells and organisms comprises introducing into a cell or organism in which a gene (referred to as a targeted gene) to be knocked down, an siRNA of about 16 to about 30 nucleotides (nt) that targets the gene and maintaining the resulting cell or organism under conditions under which RNAi occurs, resulting in degradation of the mRNA of the targeted gene, thereby producing knockdown cells or organisms. Knockdown cells and organisms produced by the present method are also the subject of embodiment of the present invention.

An embodiment of the present invention also relates to a method of examining or assessing the function of a gene in a cell or organism. In one embodiment, RNA of about 16 to about 30 nt which targets mRNA of the gene for degradation is introduced into a cell or organism in which RNAi occurs. The cell or organism is referred to as a test cell or organism. The cell or organism is referred to as a test cell organism. The test cell or organism is maintained under conditions under which degradation of mRNA of the gene occurs. The phenotype of the test cell or organism is then observed and compared to that of an appropriate control cell or organism, such as a corresponding cell or organism that is treated in the same manner except that the gene is not targeted. A 16 to 30 nt RNA that does not target the mRNA for degradation can be introduced into the control cell or organism in place of the siRNA introduced into the test cell or organism, although it is not necessary to do so. A difference between the phenotypes of the test and control cells or organisms provides information about the function of the degraded mRNA.

The RNA of about 16 to about 30 nucleotides is isolated or synthesized and then introduced into a cell or organism in which RNAi occurs (test cell or test organism). The test cell or test organism is maintained under conditions under which degradation of the mRNA occurs. The phenotype of the test cell or organism is then observed and compared to that of an appropriate control, such as a corresponding cell or organism that is treated in the same manner as the test cell or organism except that the targeted gene is not targeted. A difference between the phenotypes of the test and control cells or organisms provides information about the function of the targeted gene. The information provided may be sufficient to identify (define) the function of the gene or may be used in conjunction with information obtained from other assays or analyses to do so.

An embodiment of the present invention also encompasses a method of treating a disease or condition associated with the presence of a protein in an individual, comprising administering to the individual RNA of from about 16 to about 30 nucleotides which targets the mRNA of the protein (the mRNA that encodes the protein) for degradation. As a result, the protein is not produced or is not produced to the extent it would be in the absence of the treatment.

FIG. 14 shows that siRNAs are short RNA duplexes of generally 16 to 30 nucleotides; the sequence of the siRNA is complementary to a mRNA expressed in the cell. Exogenous siRNA duplexes are introduced into the cell via a method of transfection. The siRNA duplexes are unwound via the RNA-induced silencing complex (RISC), whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC/AGO complex, which has RNAse cleave activity. The end result is that the mRNA targeted by the siRNA is degraded, and the protein encoded by the mRNA is not produced. This causes the “knockdown” effect or reduced protein levels of the gene targeted by the siRNA compared to control treated cells.

In one embodiment, at least one strand of the RNA molecule has a 3′ overhang from about 1 to about 6 nucleotides (e.g., pyrimidine nucleotides, purine nucleotides) in length. In other embodiments, the 3′ overhang is from about 1 to about 5 nucleotides, from about 1 to about 3 nucleotides and from about 2 to about 4 nucleotides in length or, for example, the overhang can be up to 14 nucleotides if the guide strand were a 27-mer. In one embodiment the RNA molecule is double stranded, one strand has a 3′ overhang and the other strand can be blunt-ended or have an overhang. In the embodiment in which the RNA molecule is double stranded and both strands comprise an overhang, the length of the overhangs may be the same or different for each strand. In a particular embodiment, the RNA of the present invention comprises 21-27 nucleotide strands which are Watson-Crick paired and which have overhangs of from about 1 to about 3, particularly about 2, nucleotides on both 3′ ends of the RNA. In order to further enhance the stability of the RNA of the present invention, the 3′ overhangs can be stabilized against degradation. In one embodiment, the RNA is stabilized by including purine nucleotides, such as adenosine or guanosine nucleotides. Alternatively, substitution of pyrimidine nucleotides by unnatural nucleotides, e.g., substitution of uridine 2 nucleotide 3′ overhangs by 2′-deoxythymidine, is tolerated and does not affect the efficiency of RNAi. The absence of a 2′ hydroxyl significantly enhances the nuclease resistance of the overhang in tissue culture medium. The 3′-overhangs can be further stabilized by introduction of phosphorothioate groups in place of the phosphodiesters.

The 16-30 nt RNA molecules of the present invention can be obtained using a number of techniques known to those of skill in the art. For example, the RNA can be chemically synthesized or recombinantly produced using methods known in the art.

In order that the present invention may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this invention.

The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements.

The term “including” is used herein to mean, and is used interchangeably with, the phrase “including but not limited to”.

The term “or” is used herein to mean, and is used interchangeably with, the term “and/or,” unless context clearly indicates otherwise.

As used herein, “CD320” refers to the gene or protein. CD320 is also known as 8D6 antigen, CD320 antigen, 8D6A, transcobalalmin receptor, FDC-SM-8D6, FDC-Signaling Molecule 8D6, 8D6, TCBLR, TCblR, TCN2R. The term CD320 includes human CD320, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_016579.4 and NM_001165895.2; mouse CD320, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_019421.3; rat CD320, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_001014201.1. Additional examples of CD320 mRNA sequences are readily available using, e.g., GenBank. Additional information is found at FIG. 17 .

The CD320 DNA sequence from Homo sapiens is as follows: >NM_016579.4 Homo sapiens CD320 molecule (CD320), transcript variant 1, DNA

(SEQ ID NO. 935) GTGCGCGTGCGCAGGGATAAGAGAGCGGTCTGGACAGCGCGTGGCCGGC GCCGCTGTGGGGACAGCATGAGCGGCGGTTGGATGGCGCAGGTTGGAGC GTGGCGAACAGGGGCTCTGGGCCTGGCGCTGCTGCTGCTGCTCGGCCTC GGACTAGGCCTGGAGGCCGCCGCGAGCCCGCTTTCCACCCCGACCTCTG CCCAGGCCGCAGGCCCCAGCTCAGGCTCGTGCCCACCCACCAAGTTCCA GTGCCGCACCAGTGGCTTATGCGTGCCCCTCACCTGGCGCTGCGACAGG GACTTGGACTGCAGCGATGGCAGCGATGAGGAGGAGTGCAGGATTGAGC CATGTACCCAGAAAGGGCAATGCCCACCGCCCCCTGGCCTCCCCTGCCC CTGCACCGGCGTCAGTGACTGCTCTGGGGGAACTGACAAGAAACTGCGC AACTGCAGCCGCCTGGCCTGCCTAGCAGGCGAGCTCCGTTGCACGCTGA GCGATGACTGCATTCCACTCACGTGGCGCTGCGACGGCCACCCAGACTG TCCCGACTCCAGCGACGAGCTCGGCTGTGGAACCAATGAGATCCTCCCG GAAGGGGATGCCACAACCATGGGGCCCCCTGTGACCCTGGAGAGTGTCA CCTCTCTCAGGAATGCCACAACCATGGGGCCCCCTGTGACCCTGGAGAG TGTCCCCTCTGTCGGGAATGCCACATCCTCCTCTGCCGGAGACCAGTCT GGAAGCCCAACTGCCTATGGGGTTATTGCAGCTGCTGCGGTGCTCAGTG CAAGCCTGGTCACCGCCACCCTCCTCCTTTTGTCCTGGCTCCGAGCCCA GGAGCGCCTCCGCCCACTGGGGTTACTGGTGGCCATGAAGGAGTCCCTG CTGCTGTCAGAACAGAAGACCTCGCTGCCCTGAGGACAAGCACTTGCCA CCACCGTCACTCAGCCCTGGGCGTAGCCGGACAGGAGGAGAGCAGTGAT GCGGATGGGTACCCGGGCACACCAGCCCTCAGAGACCTGAGCTCTTCTG GCCACGTGGAACCTCGAACCCGAGCTCCTGCAGAAGTGGCCCTGGAGAT TGAGGGTCCCTGGACACTCCCTATGGAGATCCGGGGAGCTAGGATGGGG AACCTGCCACAGCCAGAACTGAGGGGCTGGCCCCAGGCAGCTCCCAGGG GGTAGAACGGCCCTGTGCTTAAGACACTCCTGCTGCCCCGTCTGAGGGT GGCGATTAAAGTTGCTTCACATCCTCAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAA.

A protein sequence from CD320 derived from the mRNA sequence above is as follows: >sp|Q9NPF0|CD320_HUMAN CD320 antigen OS=Homo sapiens OX=9606 GN=CD320 PE=1 SV=1

(SEQ ID NO. 936) MSGGWMAQVGAWRTGALGLALLLLLGLGLGLEAAASPLSTPTSAQAAGP SSGSCPPTKFQCRTSGLCVPLTWRCDRDLDCSDGSDEEECRIEPCTQKG QCPPPPGLPCPCTGVSDCSGGTDKKLRNCSRLACLAGELRCTLSDDCIP LTWRCDGHPDCPDSSDELGCGTNEILPEGDATTMGPPVTLESVTSLRNA TTMGPPVTLESVPSVGNATSSSAGDQSGSPTAYGVIAAAAVLSASLVTA TLLLLSWLRAQERLRPLGLLVAMKESLLLSEQKTSLP

The CD320 DNA sequence from Homo sapiens is as follows: >NM_001165895.2 Homo sapiens CD320 molecule (CD320), transcript variant 2, DNA

(SEQ ID NO. 937) GCGTGCGCGTGCGCAGGGATAAGAGAGCGGTCTGGACAGCGCGTGGCCG GCGCCGCTGTGGGGACAGCATGAGCGGCGGTTGGATGGCGCAGGTTGGA GCGTGGCGAACAGGGGCTCTGGGCCTGGCGCTGCTGCTGCTGCTCGGCC TCGGACTAGGCCTGGAGGCCGCCGCGAGCCCGCTTTCCACCCCGACCTC TGCCCAGGCCGCAGGGATTGAGCCATGTACCCAGAAAGGGCAATGCCCA CCGCCCCCTGGCCTCCCCTGCCCCTGCACCGGCGTCAGTGACTGCTCTG GGGGAACTGACAAGAAACTGCGCAACTGCAGCCGCCTGGCCTGCCTAGC AGGCGAGCTCCGTTGCACGCTGAGCGATGACTGCATTCCACTCACGTGG CGCTGCGACGGCCACCCAGACTGTCCCGACTCCAGCGACGAGCTCGGCT GTGGAACCAATGAGATCCTCCCGGAAGGGGATGCCACAACCATGGGGCC CCCTGTGACCCTGGAGAGTGTCACCTCTCTCAGGAATGCCACAACCATG GGGCCCCCTGTGACCCTGGAGAGTGTCCCCTCTGTCGGGAATGCCACAT CCTCCTCTGCCGGAGACCAGTCTGGAAGCCCAACTGCCTATGGGGTTAT TGCAGCTGCTGCGGTGCTCAGTGCAAGCCTGGTCACCGCCACCCTCCTC CTTTTGTCCTGGCTCCGAGCCCAGGAGCGCCTCCGCCCACTGGGGTTAC TGGTGGCCATGAAGGAGTCCCTGCTGCTGTCAGAACAGAAGACCTCGCT GCCCTGAGGACAAGCACTTGCCACCACCGTCACTCAGCCCTGGGCGTAG CCGGACAGGAGGAGAGCAGTGATGCGGATGGGTACCCGGGCACACCAGC CCTCAGAGACCTGAGCTCTTCTGGCCACGTGGAACCTCGAACCCGAGCT CCTGCAGAAGTGGCCCTGGAGATTGAGGGTCCCTGGACACTCCCTATGG AGATCCGGGGAGCTAGGATGGGGAACCTGCCACAGCCAGAACTGAGGGG CTGGCCCCAGGCAGCTCCCAGGGGGTAGAACGGCCCTGTGCTTAAGACA CTCCTGCTGCCCCGTCTGAGGGTGGCAATTAAAGTTGCTTCACATCCTC

A protein sequence from CD320 derived from the DNA sequence above is as follows: >sp|Q9NPF0-2|CD320_HUMAN Isoform 2 of CD320 antigen OS=Homo sapiens OX=9606 GN=CD320

(SEQ ID NO. 938) MSGGWMAQVGAWRTGALGLALLLLLGLGLGLEAAASPLSTPTSAQAAGI EPCTQKGQCPPPPGLPCPCTGVSDCSGGTDKKLRNCSRLACLAGELRCT LSDDCIPLTWRCDGHPDCPDSSDELGCGTNEILPEGDATTMGPPVTLES VTSLRNATTMGPPVTLESVPSVGNATSSSAGDQSGSPTAYGVIAAAAVL SASLVTATLLLLSWLRAQERLRPLGLLVAMKESLLLSEQKTSLP 

Further, as used herein, “LRP2” refers to the gene or protein. LRP2 is also known as megalin, LRP-2, Glycoprotein 330, DBS, GP330, Gp330, Calcium Sensor Protein, Heymann Nephritis Antigen Homolog, Low-Density Lipoprotein Receptor-Related Protein 2, EC 1.1.2.3, EC 3.4.21.9, LDL receptor related protein 2. The term LRP2 includes human LRP2, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_004525.3; mouse LRP2, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_001081088.2; rat LRP2, the amino acid and nucleotide sequence of which may be found in, for example, GenBank Accession No. NM_030827.1. Additional examples of LRP2 mRNA sequences are readily available using, e.g., GenBank. Additional information is found at FIG. 18 .

One example of LRP2 is: >NM_004525.3 Homo sapiens LDL receptor related protein 2 (LRP2), DNA:

(SEQ ID NO. 939) GGTCTAAAGGGCTTTATGCACTGTCTGGAGGGTGGGGACTGGCGCGGGTAGAAAACGGGATGCCTCGGGC GTGGGGGCAGGCTTTTGGCCACTAGGAGCTGGCGGAGGTGCAGACCTAAAGGAGCGTTCGCTAGCAGAGG CGCTGCCGGTGCGGTGTGCTACGCGCGCCCACCTCCCGGGGAAGGAACGGCGAGGCCGGGGACCGTCGCG GAGATGGATCGCGGGCCGGCAGCAGTGGCGTGCACGCTGCTCCTGGCTCTCGTCGCCTGCCTAGCGCCGG CCAGTGGCCAAGAATGTGACAGTGCGCATTTTCGCTGTGGAAGTGGGCATTGCATCCCTGCAGACTGGAG GTGTGATGGGACCAAAGACTGTTCAGATGACGCGGATGAAATTGGCTGCGCTGTTGTGACCTGCCAGCAG GGCTATTTCAAGTGCCAGAGTGAGGGACAATGCATCCCCAACTCCTGGGTGTGTGACCAAGATCAAGACT GTGATGATGGCTCAGATGAACGTCAAGATTGCTCACAAAGTACATGCTCAAGTCATCAGATAACATGCTC CAATGGTCAGTGTATCCCAAGTGAATACAGGTGCGACCACGTCAGAGACTGCCCCGATGGAGCTGATGAG AATGACTGCCAGTACCCAACATGTGAGCAGCTTACTTGTGACAATGGGGCCTGCTATAACACCAGTCAGA AGTGTGATTGGAAAGTTGATTGCAGGGACTCCTCAGATGAAATCAACTGCACTGAGATATGCTTGCACAA TGAGTTTTCATGTGGCAATGGAGAGTGTATCCCTCGTGCTTATGTCTGTGACCATGACAATGATTGCCAA GACGGCAGTGACGAACATGCTTGCAACTATCCGACCTGCGGTGGTTACCAGTTCACTTGCCCCAGTGGCC GATGCATTTATCAAAACTGGGTTTGTGATGGAGAAGATGACTGTAAAGATAATGGAGATGAAGATGGATG TGAAAGCGGTCCTCATGATGTTCATAAATGTTCCCCAAGAGAATGGTCTTGCCCAGAGTCGGGACGATGC ATCTCCATTTATAAAGTTTGTGATGGGATTTTAGATTGCCCAGGAAGAGAAGATGAAAACAACACTAGTA CCGGAAAATACTGTAGTATGACTCTGTGCTCTGCCTTGAACTGCCAGTACCAGTGCCATGAGACGCCGTA TGGAGGAGCGTGTTTTTGTCCCCCAGGTTATATCATCAACCACAATGACAGCCGTACCTGTGTTGAGTTT GATGATTGCCAGATATGGGGAATTTGTGACCAGAAGTGTGAAAGCCGACCTGGCCGTCACCTGTGCCACT GTGAAGAAGGGTATATCTTGGAGCGTGGACAGTATTGCAAAGCTAATGATTCCTTTGGCGAGGCCTCCAT TATCTTCTCCAATGGTCGGGATTTGTTAATTGGTGATATTCATGGAAGGAGCTTCCGGATCCTAGTGGAG TCTCAGAATCGTGGAGTGGCCGTGGGTGTGGCTTTCCACTATCACCTGCAAAGAGTTTTTTGGACAGACA CCGTGCAAAATAAGGTTTTTTCAGTTGACATTAATGGTTTAAATATCCAAGAGGTTCTCAATGTTTCTGT TGAAACCCCAGAGAACCTGGCTGTGGACTGGGTTAATAATAAAATCTATCTAGTGGAAACCAAGGTCAAC CGCATAGATATGGTAAATTTGGATGGAAGCTATCGGGTTACCCTTATAACTGAAAACTTGGGGCATCCTA GAGGAATTGCCGTGGACCCAACTGTTGGTTATTTATTTTTCTCAGATTGGGAGAGCCTTTCTGGGGAACC TAAGCTGGAAAGGGCATTCATGGATGGCAGCAACCGTAAAGACTTGGTGAAAACAAAGCTGGGATGGCCT GCTGGGGTAACTCTGGATATGATATCGAAGCGTGTTTACTGGGTTGACTCTCGGTTTGATTACATTGAAA CTGTAACTTATGATGGAATTCAAAGGAAGACTGTAGTTCATGGAGGCTCCCTCATTCCTCATCCCTTTGG AGTAAGCTTATTTGAAGGTCAGGTGTTCTTTACAGATTGGACAAAGATGGCCGTGCTGAAGGCAAACAAG TTCACAGAGACCAACCCACAAGTGTACTACCAGGCTTCCCTGAGGCCCTATGGAGTGACTGTTTACCATT CCCTCAGACAGCCCTATGCTACCAATCCGTGTAAAGATAACAATGGGGGCTGTGAGCAGGTCTGTGTCCT CAGCCACAGAACAGATAATGATGGTTTGGGTTTCCGTTGCAAGTGCACATTCGGCTTCCAACTGGATACA GATGAGCGCCACTGCATTGCTGTTCAGAATTTCCTCATTTTTTCATCCCAAGTTGCTATTCGTGGGATCC CGTTCACCTTGTCTACCCAGGAAGATGTCATGGTTCCAGTTTCGGGGAATCCTTCTTTCTTTGTCGGGAT TGATTTTGACGCCCAGGACAGCACTATCTTTTTTTCAGATATGTCAAAACACATGATTTTTAAGCAAAAG ATTGATGGCACAGGAAGAGAAATTCTCGCAGCTAACAGGGTGGAAAATGTTGAAAGTTTGGCTTTTGATT GGATTTCAAAGAATCTCTATTGGACAGACTCTCATTACAAGAGTATCAGTGTCATGAGGCTAGCTGATAA AACGAGACGCACAGTAGTTCAGTATTTAAATAACCCACGGTCGGTGGTAGTTCATCCTTTTGCCGGGTAT CTATTCTTCACTGATTGGTTCCGTCCTGCTAAAATTATGAGAGCATGGAGTGACGGATCTCACCTCTTGC CTGTAATAAACACTACTCTTGGATGGCCCAATGGCTTGGCCATCGATTGGGCTGCTTCACGATTGTACTG GGTAGATGCCTATTTTGATAAAATTGAGCACAGCACCTTTGATGGTTTAGACAGAAGAAGACTGGGCCAT ATAGAGCAGATGACACATCCGTTTGGACTTGCCATCTTTGGAGAGCATTTATTTTTTACTGACTGGAGAC TGGGTGCCATTATTCGAGTCAGGAAAGCAGATGGTGGAGAAATGACAGTTATCCGAAGTGGCATTGCTTA CATACTGCATTTGAAATCGTATGATGTCAACATCCAGACTGGTTCTAACGCCTGTAATCAACCCACGCAT CCTAACGGTGACTGCAGCCACTTCTGCTTCCCGGTGCCAAATTTCCAGCGAGTGTGTGGGTGCCCTTATG GAATGAGGCTGGCTTCCAATCACTTGACATGCGAGGGGGACCCAACCAATGAACCACCCACAGAGCAGTG TGGCTTATTTTCCTTCCCCTGTAAAAATGGCAGATGTGTGCCCAATTACTATCTCTGTGATGGAGTCGAT GATTGTCATGATAACAGTGATGAGCAACTATGTGGCACACTTAATAATACCTGTTCATCTTCGGCGTTCA CCTGTGGCCATGGGGAGTGCATTCCTGCACACTGGCGCTGTGACAAACGCAACGACTGTGTGGATGGCAG TGATGAGCACAACTGCCCCACCCACGCACCTGCTTCCTGCCTTGACACCCAATACACCTGTGATAATCAC CAGTGTATCTCAAAGAACTGGGTCTGTGACACAGACAATGATTGTGGGGATGGATCTGATGAAAAGAACT GCAATTCGACAGAGACATGCCAACCTAGTCAGTTTAATTGCCCCAATCATCGATGTATTGACCTATCGTT TGTCTGTGATGGTGACAAGGATTGTGTTGATGGATCTGATGAGGTTGGTTGTGTATTAAACTGTACTGCT TCTCAATTCAAGTGTGCCAGTGGGGATAAATGTATTGGCGTCACAAATCGTTGTGATGGTGTTTTTGATT GCAGTGACAACTCGGATGAAGCAGGCTGTCCAACCAGGCCTCCTGGTATGTGCCACTCAGATGAATTTCA GTGCCAAGAAGATGGTATCTGCATCCCGAACTTCTGGGAATGTGATGGGCATCCAGACTGCCTCTATGGA TCTGATGAGCACAATGCCTGTGTCCCCAAGACTTGCCCTTCATCATATTTCCACTGTGACAACGGAAACT GCATCCACAGGGCATGGCTCTGTGATCGGGACAATGACTGCGGGGATATGAGTGATGAGAAGGACTGCCC TACTCAGCCCTTTCGCTGTCCTAGTTGGCAATGGCAGTGTCTTGGCCATAACATCTGTGTGAATCTGAGT GTAGTGTGTGATGGCATCTTTGACTGCCCCAATGGGACAGATGAGTCCCCACTTTGCAATGGGAACAGCT GCTCAGATTTCAATGGTGGTTGTACTCACGAGTGTGTTCAAGAGCCCTTTGGGGCTAAATGCCTATGTCC ATTGGGATTCTTACTTGCCAATGATTCTAAGACCTGTGAAGACATAGATGAATGTGATATTCTAGGCTCT TGTAGCCAGCACTGTTACAATATGAGAGGTTCTTTCCGGTGCTCGTGTGATACAGGCTACATGTTAGAAA GTGATGGGAGGACTTGCAAAGTTACAGCATCTGAGAGTCTGCTGTTACTTGTGGCAAGTCAGAACAAAAT TATTGCCGACAGTGTCACCTCCCAGGTCCACAATATCTATTCATTGGTCGAGAATGGTTCTTACATTGTA GCTGTTGATTTTGATTCAATTAGTGGTCGTATCTTTTGGTCTGATGCAACTCAGGGTAAAACCTGGAGTG CGTTTCAAAATGGAACGGACAGAAGAGTGGTATTTGACAGTAGCATCATCTTGACTGAAACTATTGCAAT AGATTGGGTAGGTCGTAATCTTTACTGGACAGACTATGCTCTGGAAACAATTGAAGTCTCCAAAATTGAT GGGAGCCACAGGACTGTGCTGATTAGTAAAAACCTAACAAATCCAAGAGGACTAGCATTAGATCCCAGAA TGAATGAGCATCTACTGTTCTGGTCTGACTGGGGCCACCACCCTCGCATCGAGCGAGCCAGCATGGACGG CAGCATGCGCACTGTCATTGTCCAGGACAAGATCTTCTGGCCCTGCGGCTTAACTATTGACTACCCCAAC AGACTGCTCTACTTCATGGACTCCTATCTTGATTACATGGACTTTTGTGATTATAATGGACACCATCGGA GACAGGTGATAGCCAGTGATTTGATTATACGGCACCCCTATGCCCTAACTCTCTTTGAAGACTCTGTGTA CTGGACTGACCGTGCTACTCGTCGGGTTATGCGAGCCAACAAGTGGCATGGAGGGAACCAGTCAGTTGTA ATGTATAATATTCAATGGCCCCTTGGGATTGTTGCGGTTCATCCTTCGAAACAACCAAATTCCGTGAATC CATGTGCCTTTTCCCGCTGCAGCCATCTCTGCCTGCTTTCCTCACAGGGGCCTCATTTTTACTCCTGTGT TTGTCCTTCAGGATGGAGTCTGTCTCCTGATCTCCTGAATTGCTTGAGAGATGATCAACCTTTCTTAATA ACTGTAAGGCAACATATAATTTTTGGAATCTCCCTTAATCCTGAGGTGAAGAGCAATGATGCTATGGTCC CCATAGCAGGGATACAGAATGGTTTAGATGTTGAATTTGATGATGCTGAGCAATACATCTATTGGGTTGA AAATCCAGGTGAAATTCACAGAGTGAAGACAGATGGCACCAACAGGACAGTATTTGCTTCTATATCTATG GTGGGGCCTTCTATGAACCTGGCCTTAGATTGGATTTCAAGAAACCTTTATTCTACCAATCCTAGAACTC AGTCAATCGAGGTTTTGACACTCCACGGAGATATCAGATACAGAAAAACATTGATTGCCAATGATGGGAC AGCTCTTGGAGTTGGCTTTCCAATTGGCATAACTGTTGATCCTGCTCGTGGGAAGCTGTACTGGTCAGAC CAAGGAACTGACAGTGGGGTTCCTGCCAAGATCGCCAGTGCTAACATGGATGGCACATCTGTGAAAACTC TCTTTACTGGGAACCTCGAACACCTGGAGTGTGTCACTCTTGACATCGAAGAGCAGAAACTCTACTGGGC AGTCACTGGAAGAGGAGTGATTGAAAGAGGAAACGTGGATGGAACAGATCGAATGATCCTGGTACACCAG CTTTCCCACCCCTGGGGAATTGCAGTCCATGATTCTTTCCTTTATTATACTGATGAACAGTATGAGGTCA TTGAAAGAGTTGATAAGGCCACTGGGGCCAACAAAATAGTCTTGAGAGATAATGTTCCAAATCTGAGGGG TCTTCAAGTTTATCACAGACGCAATGCCGCCGAATCCTCAAATGGCTGTAGCAACAACATGAATGCCTGT CAGCAGATTTGCCTGCCTGTACCAGGAGGATTGTTTTCCTGCGCCTGTGCCACTGGATTTAAACTCAATC CTGATAATCGGTCCTGCTCTCCATATAACTCTTTCATTGTTGTTTCAATGCTGTCTGCAATCAGAGGCTT TAGCTTGGAATTGTCAGATCATTCAGAAACCATGGTGCCGGTGGCAGGCCAAGGACGAAACGCACTGCAT GTGGATGTGGATGTGTCCTCTGGCTTTATTTATTGGTGTGATTTTAGCAGCTCAGTGGCATCTGATAATG CGATCCGTAGAATTAAACCAGATGGATCTTCTCTGATGAACATTGTGACACATGGAATAGGAGAAAATGG AGTCCGGGGTATTGCAGTGGATTGGGTAGCAGGAAATCTTTATTTCACCAATGCCTTTGTTTCTGAAACA CTGATAGAAGTTCTGCGGATCAATACTACTTACCGCCGTGTTCTTCTTAAAGTCACAGTGGACATGCCTA GGCATATTGTTGTAGATCCCAAGAACAGATACCTCTTCTGGGCTGACTATGGGCAGAGACCAAAGATTGA GCGTTCTTTCCTTGACTGTACCAATCGAACAGTGCTTGTGTCAGAGGGCATTGTCACACCACGGGGCTTG GCAGTGGACCGAAGTGATGGCTACGTTTATTGGGTTGATGATTCTTTAGATATAATTGCAAGGATTCGTA TCAATGGAGAGAACTCTGAAGTGATTCGTTATGGCAGTCGTTACCCAACTCCTTATGGCATCACTGTTTT TGAAAATTCTATCATATGGGTAGATAGGAATTTGAAAAAGATCTTCCAAGCCAGCAAGGAACCAGAGAAC ACAGAGCCACCCACAGTGATAAGAGACAATATCAACTGGCTAAGAGATGTGACCATCTTTGACAAGCAAG TCCAGCCCCGGTCACCAGCAGAGGTCAACAACAACCCTTGCTTGGAAAACAATGGTGGGTGCTCTCATCT CTGCTTTGCTCTGCCTGGATTGCACACCCCAAAATGTGACTGTGCCTTTGGGACCCTGCAAAGTGATGGC AAGAATTGTGCCATTTCAACAGAAAATTTCCTCATCTTTGCCTTGTCTAATTCCTTGAGAAGCTTACACT TGGACCCTGAAAACCATAGCCCACCTTTCCAAACAATAAATGTGGAAAGAACTGTCATGTCTCTAGACTA TGACAGTGTAAGTGATAGAATCTACTTCACACAAAATTTAGCCTCTGGAGTTGGACAGATTTCCTATGCC ACCCTGTCTTCAGGGATCCATACTCCAACTGTCATTGCTTCAGGTATAGGGACTGCTGATGGCATTGCCT TTGACTGGATTACTAGAAGAATTTATTACAGTGACTACCTCAACCAGATGATTAATTCCATGGCTGAAGA TGGGTCTAACCGCACTGTGATAGCCCGCGTTCCAAAACCAAGAGCAATTGTGTTAGATCCCTGCCAAGGG TACCTGTACTGGGCTGACTGGGATACACATGCCAAAATCGAGAGAGCCACATTGGGAGGAAACTTCCGCG TACCCATTGTGAACAGCAGTCTGGTCATGCCCAGTGGGCTGACTCTGGACTATGAAGAGGACCTTCTCTA CTGGGTGGATGCTAGTCTGCAGAGGATTGAACGCAGCACTCTGACGGGCGTGGATCGTGAAGTCATTGTC AATGCAGCCGTTCATGCTTTTGGCTTGACTCTCTATGGCCAGTATATTTACTGGACTGACTTGTACACAC AAAGAATTTACCGAGCTAACAAATATGACGGGTCAGGTCAGATTGCAATGACCACAAATTTGCTCTCCCA GCCCAGGGGAATCAACACTGTTGTGAAGAACCAGAAACAACAGTGTAACAATCCTTGTGAACAGTTTAAT GGGGGCTGCAGCCATATCTGTGCACCAGGTCCAAATGGTGCCGAGTGCCAGTGTCCACATGAGGGCAACT GGTATTTGGCCAACAACAGGAAGCACTGCATTGTGGACAATGGTGAACGATGTGGTGCATCTTCCTTCAC CTGCTCCAATGGGCGCTGCATCTCGGAAGAGTGGAAGTGTGATAATGACAACGACTGTGGGGATGGCAGT GATGAGATGGAAAGTGTCTGTGCACTTCACACCTGCTCACCGACAGCCTTCACCTGTGCCAATGGGCGAT GTGTCCAATACTCTTACCGCTGTGATTACTACAATGACTGTGGTGATGGCAGTGATGAGGCAGGGTGCCT GTTCAGGGACTGCAATGCCACCACGGAGTTTATGTGCAATAACAGAAGGTGCATACCTCGTGAGTTTATC TGCAATGGTGTAGACAACTGCCATGATAATAACACTTCAGATGAGAAAAATTGCCCTGATCGCACTTGCC AGTCTGGATACACAAAATGTCATAATTCAAATATTTGTATTCCTCGCGTTTATTTGTGTGACGGAGACAA TGACTGTGGAGATAACAGTGATGAAAACCCTACTTATTGCACCACTCACACGTGCAGCAGCAGTGAGTTC CAATGCGCATCTGGGCGCTGTATTCCTCAACATTGGTATTGTGATCAAGAAACAGATTGTTTTGATGCCT CTGATGAACCTGCCTCTTGTGGTCACTCTGAGCGAACATGCCTAGCTGATGAGTTCAAGTGTGATGGTGG GAGGTGCATCCCAAGCGAATGGATCTGTGACGGTGATAATGACTGTGGGGATATGAGTGACGAGGATAAA AGGCACCAGTGTCAGAATCAAAACTGCTCGGATTCCGAGTTTCTCTGTGTAAATGACAGACCTCCGGACA GGAGGTGCATTCCCCAGTCTTGGGTCTGTGATGGCGATGTGGATTGTACTGACGGCTACGATGAGAATCA GAATTGCACCAGGAGAACTTGCTCTGAAAATGAATTCACCTGTGGTTACGGACTGTGTATCCCAAAGATA TTCAGGTGTGACCGGCACAATGACTGTGGTGACTATAGCGACGAGAGGGGCTGCTTATACCAGACTTGCC AACAGAATCAGTTTACCTGTCAGAACGGGCGCTGCATTAGTAAAACCTTCGTCTGTGATGAGGATAATGA CTGTGGAGACGGATCTGATGAGCTGATGCACCTGTGCCACACCCCAGAACCCACGTGTCCACCTCACGAG TTCAAGTGTGACAATGGGCGCTGCATCGAGATGATGAAACTCTGCAACCACCTAGATGACTGTTTGGACA ACAGCGATGAGAAAGGCTGTGGCATTAATGAATGCCATGACCCTTCAATCAGTGGCTGCGATCACAACTG CACAGACACCTTAACCAGTTTCTATTGTTCCTGTCGTCCTGGTTACAAGCTCATGTCTGACAAGCGGACT TGTGTTGATATTGATGAATGCACAGAGATGCCTTTTGTCTGTAGCCAGAAGTGTGAGAATGTAATAGGCT CCTACATCTGTAAGTGTGCCCCAGGCTACCTCCGAGAACCAGATGGAAAGACCTGCCGGCAAAACAGTAA CATCGAACCCTATCTCATTTTTAGCAACCGTTACTATTTGAGAAATTTAACTATAGATGGCTATTTTTAC TCCCTCATCTTGGAAGGACTGGACAATGTTGTGGCATTAGATTTTGACCGAGTAGAGAAGAGATTGTATT GGATTGATACACAGAGGCAAGTCATTGAGAGAATGTTTCTGAATAAGACAAACAAGGAGACAATCATAAA CCACAGACTACCAGCTGCAGAAAGTCTGGCTGTAGACTGGGTTTCCAGAAAGCTCTACTGGTTGGATGCC CGCCTGGATGGCCTCTTTGTCTCTGACCTCAATGGTGGACACCGCCGCATGCTGGCCCAGCACTGTGTGG ATGCCAACAACACCTTCTGCTTTGATAATCCCAGAGGACTTGCCCTTCACCCTCAATATGGGTACCTCTA CTGGGCAGACTGGGGTCACCGCGCATACATTGGGAGAGTAGGCATGGATGGAACCAACAAGTCTGTGATA ATCTCCACCAAGTTAGAGTGGCCTAATGGCATCACCATTGATTACACCAATGATCTACTCTACTGGGCAG ATGCCCACCTGGGTTACATAGAGTACTCTGATTTGGAGGGCCACCATCGACACACGGTGTATGATGGGGC ACTGCCTCACCCTTTCGCTATTACCATTTTTGAAGACACTATTTATTGGACAGATTGGAATACAAGGACA GTGGAAAAGGGAAACAAATATGATGGATCAAATAGACAGACACTGGTGAACACAACACACAGACCATTTG ACATCCATGTGTACCATCCATATAGGCAGCCCATTGTGAGCAATCCCTGTGGTACCAACAATGGTGGCTG TTCTCATCTCTGCCTCATCAAGCCAGGAGGAAAAGGGTTCACTTGCGAGTGTCCAGATGACTTCCGCACC CTTCAGCTGAGTGGCAGCACCTACTGCATGCCCATGTGCTCCAGCACCCAGTTCCTGTGCGCTAACAATG AAAAGTGCATTCCTATCTGGTGGAAATGTGATGGACAGAAAGACTGCTCAGATGGCTCTGATGAACTGGC CCTTTGCCCGCAGCGCTTCTGCCGACTGGGACAGTTCCAGTGCAGTGACGGCAACTGCACCAGCCCGCAG ACTTTATGCAATGCTCACCAAAATTGCCCTGATGGGTCTGATGAAGACCGTCTTCTTTGTGAGAATCACC ACTGTGACTCCAATGAATGGCAGTGCGCCAACAAACGTTGCATCCCAGAATCCTGGCAGTGTGACACATT TAACGACTGTGAGGATAACTCAGATGAAGACAGTTCCCACTGTGCCAGCAGGACCTGCCGGCCGGGCCAG TTTCGGTGTGCTAATGGCCGCTGCATCCCGCAGGCCTGGAAGTGTGATGTGGATAATGATTGTGGAGACC ACTCGGATGAGCCCATTGAAGAATGCATGAGCTCTGCCCATCTCTGTGACAACTTCACAGAATTCAGCTG CAAAACAAATTACCGCTGCATCCCAAAGTGGGCCGTGTGCAATGGTGTAGATGACTGCAGGGACAACAGT GATGAGCAAGGCTGTGAGGAGAGGACATGCCATCCTGTGGGGGATTTCCGCTGTAAAAATCACCACTGCA TCCCTCTTCGTTGGCAGTGTGATGGGCAAAATGACTGTGGAGATAACTCAGATGAGGAAAACTGTGCTCC CCGGGAGTGCACAGAGAGCGAGTTTCGATGTGTCAATCAGCAGTGCATTCCCTCGCGATGGATCTGTGAC CATTACAACGACTGTGGGGACAACTCAGATGAACGGGACTGTGAGATGAGGACCTGCCATCCTGAATATT TTCAGTGTACAAGTGGACATTGTGTACACAGTGAACTGAAATGCGATGGATCCGCTGACTGTTTGGATGC GTCTGATGAAGCTGATTGTCCCACACGCTTTCCTGATGGTGCATACTGCCAGGCTACTATGTTCGAATGC AAAAACCATGTTTGTATCCCGCCATATTGGAAATGTGATGGCGATGATGACTGTGGCGATGGTTCAGATG AAGAACTTCACCTGTGCTTGGATGTTCCCTGTAATTCACCAAACCGTTTCCGGTGTGACAACAATCGCTG CATTTATAGTCATGAGGTGTGCAATGGTGTGGATGACTGTGGAGATGGAACTGATGAGACAGAGGAGCAC TGTAGAAAACCGACCCCTAAACCTTGTACAGAATATGAATATAAGTGTGGCAATGGGCATTGCATTCCAC ATGACAATGTGTGTGATGATGCCGATGACTGTGGTGACTGGTCCGATGAACTGGGTTGCAATAAAGGAAA AGAAAGAACATGTGCTGAAAATATATGCGAGCAAAATTGTACCCAATTAAATGAAGGAGGATTTATCTGC TCCTGTACAGCTGGGTTCGAAACCAATGTTTTTGACAGAACCTCCTGTCTAGATATCAATGAATGTGAAC AATTTGGGACTTGTCCCCAGCACTGCAGAAATACCAAAGGAAGTTATGAGTGTGTCTGTGCTGATGGCTT CACGTCTATGAGTGACCGCCCTGGAAAACGATGTGCAGCTGAGGGTAGCTCTCCTTTGTTGCTACTGCCT GACAATGTCCGAATTCGAAAATATAATCTCTCATCTGAGAGGTTCTCAGAGTATCTTCAAGATGAGGAAT ATATCCAAGCTGTTGATTATGATTGGGATCCCAAGGACATAGGCCTCAGTGTTGTGTATTACACTGTGCG AGGGGAGGGCTCTAGGTTTGGTGCTATCAAACGTGCCTACATCCCCAACTTTGAATCCGGCCGCAATAAT CTTGTGCAGGAAGTTGACCTGAAACTGAAATACGTAATGCAGCCAGATGGAATAGCAGTGGACTGGGTTG GAAGGCATATTTACTGGTCAGATGTCAAGAATAAACGCATTGAGGTGGCTAAACTTGATGGAAGGTACAG AAAGTGGCTGATTTCCACTGACCTGGACCAACCAGCTGCTATTGCTGTGAATCCCAAACTAGGGCTTATG TTCTGGACTGACTGGGGAAAGGAACCTAAAATCGAGTCTGCCTGGATGAATGGAGAGGACCGCAACATCC TGGTTTTCGAGGACCTTGGTTGGCCAACTGGCCTTTCTATCGATTATTTGAACAATGACCGAATCTACTG GAGTGACTTCAAGGAGGACGTTATTGAAACCATAAAATATGATGGGACTGATAGGAGAGTCATTGCAAAG GAAGCAATGAACCCTTACAGCCTGGACATCTTTGAAGACCAGTTATACTGGATATCTAAGGAAAAGGGAG AAGTATGGAAACAAAATAAATTTGGGCAAGGAAAGAAAGAGAAAACGCTGGTAGTGAACCCTTGGCTCAC TCAAGTTCGAATCTTTCATCAACTCAGATACAATAAGTCAGTGCCCAACCTTTGCAAACAGATCTGCAGC CACCTCTGCCTTCTGAGACCTGGAGGATACAGCTGTGCCTGTCCCCAAGGCTCCAGCTTTATAGAGGGGA GCACCACTGAGTGTGATGCAGCCATCGAACTGCCTATCAACCTGCCCCCCCCATGCAGGTGCATGCACGG AGGAAATTGCTATTTTGATGAGACTGACCTCCCCAAATGCAAGTGTCCTAGCGGCTACACCGGAAAATAT TGTGAAATGGCGTTTTCAAAAGGCATCTCTCCAGGAACAACCGCAGTAGCTGTGCTGTTGACAATCCTCT TGATCGTCGTAATTGGAGCTCTGGCAATTGCAGGATTCTTCCACTATAGAAGGACCGGCTCCCTTTTGCC TGCTCTGCCCAAGCTGCCAAGCTTAAGCAGTCTCGTCAAGCCCTCTGAAAATGGGAATGGGGTGACCTTC AGATCAGGGGCAGATCTTAACATGGATATTGGAGTGTCTGGTTTTGGACCTGAGACTGCTATTGACAGGT CAATGGCAATGAGTGAAGACTTTGTCATGGAAATGGGGAAGCAGCCCATAATATTTGAAAACCCAATGTA CTCAGCCAGAGACAGTGCTGTCAAAGTGGTTCAGCCAATCCAGGTGACTGTATCTGAAAATGTGGATAAT AAGAATTATGGAAGTCCCATAAACCCTTCTGAGATAGTTCCAGAGACAAACCCAACTTCACCAGCTGCTG ATGGAACTCAGGTGACAAAATGGAATCTCTTCAAACGAAAATCTAAACAAACTACCAACTTTGAAAATCC AATCTATGCACAGATGGAGAACGAGCAAAAGGAAAGTGTTGCTGCGACACCACCTCCATCACCTTCGCTC CCTGCTAAGCCTAAGCCTCCTTCGAGAAGAGACCCAACTCCAACCTATTCTGCAACAGAAGACACTTTTA AAGACACCGCAAATCTTGTTAAAGAAGACTCTGAAGTATAGCTATACCAGCTATTTAGGGAATAATTAGA AACACACTTTTGCACATATATTTTTTACAAACAGATGAAAAAAGTTAACATTCAGTACTTTATGAAAAAA ATATATTTTTCCCTGTTTGCCTATAGTTGGAGGTATCCTGTGTGTCTTTTTTTACTTATGCCGTCTCATA TTTTTACAAATAATTATCACAATGTACTATATGTATATCTTTGCACTGAAGTTGTCTGAAGGTAATACTA TAAATATATTGTATATTTGTAAATTTTGGAAAGATTATCCTGTTACTGAATTTGCTAATAAAGATGTCTG CTGATTTGGTTGGTGATCATTATAGTAAATGATCCAACAAGAAAAGGAATTGACTGGGGACCTTTAGCCG TGTCTAAAGAAGAGGCACCACTCATATTTCCTATAAAATTATCTAGGAAAGGAATCCAGGCCCCGCTCTT GGGTCCATTTTTACACATTAGCACTTAATTAATGTTCAATATTACATGTCAATTTGATTAATGGCTATGT TGATAGGGGCCACTATGTGTTGTATAGACATCTGGACTTGACTGTAGACTCCTCAGATAATACAGAAGGT AGGAAAAGCAATTCAGTTTGGCCCTTCTGTGTGTTGGCATTGTCTAACCAGAACTCTCTGTTTCATGTGT GTTCTCTCACTAGCTGCCAAGACAACATTTTTATTTGTGATGTCTATGAGGAAATCCCATATCATTAAGT GCCAGTGTCCTGCATTGAGTTTGTGGTTAATTAAATGAGCTCTTCTGCTGATGGACCCTGGAGCAATTTC TCCCCTCACCTGACATTCAAGGTGGTCACCTGCCCTAGTAGTTGGAGCTCAGTAGCTGAATTTCTGAAAC CAAATCTGTGTCTTCATAAAATAAGGTGCAAAAAAAAAAAATACCAGTTAAGTAAAGCCTCAACTGGGTT TTTGTTTCTATGAAAATATCATTATAATCACTATTTATTTCCTAAGTTGAACCTGAATAGAAAGGGAAAC CATTCTTATTAAGCTTTTTATTAGGCCCTGTGGCTAAATGTGTACATTTATATTAGAATGTACTGTACAG TCCAGATCTTTTCTTTAATTCTTATTGGTTTTTTTTTTTTTTTTTTTTTTAGAGATGGAGTCTTGCTATA TTGCCAAGGCTGATCTTGAAGTCCTGGGCTCAAGTGATCCTCCCACCTCAGCCTCCTGAGTGGTTGGGGT TACGGGCGTGAGCCACTGTGCCTGGCTTCCAGCTCTCCTCTTAAATAGTGGGTATAGTCTGCACAACAGG AACCATGGCAGGAATATACACTTTCCCATAGCAAATAGCATACCTGACTCTCTGTGCTAATATTGCACAT TTGTTAAACAATGAATGAATGGATGGATGGATGGATGGATGAATGAATGAAACATATACTACTGATTATT TTATTCCAGAGTTCTCAAAATATTTGTTGCTGATATTTTGAGTGCTGACTGTAATTACTTTGATTAGATA AACAACTGGAAATAATGCTGCTGAAAAAGTTCTAATAAATGTGTATTTTATCAGA.

One example of a protein sequence from the above LRP2 DNA is: >sp|P98164|LRP2_HUMAN Low-density lipoprotein receptor-related protein 2 OS=Homo sapiens OX=9606 GN=LRP2 PE=1 SV=3

(SEQ ID NO. 940) MDRGPAAVACTLLLALVACLAPASGQECDSAHFRCGSGHCIPADWRCDG TKDCSDDADEIGCAVVTCQQGYFKCQSEGQCIPNSWVCDQDQDCDDGSD ERQDCSQSTCSSHQITCSNGQCIPSEYRCDHVRDCPDGADENDCQYPTC EQLTCDNGACYNTSQKCDWKVDCRDSSDEINCTEICLHNEFSCGNGECI PRAYVCDHDNDCQDGSDEHACNYPTCGGYQFTCPSGRCIYQNWVCDGED DCKDNGDEDGCESGPHDVHKCSPREWSCPESGRCISIYKVCDGILDCPG REDENNTSTGKYCSMTLCSALNCQYQCHETPYGGACFCPPGYIINHNDS RTCVEFDDCQIWGICDQKCESRPGRHLCHCEEGYILERGQYCKANDSFG EASIIFSNGRDLLIGDIHGRSFRILVESQNRGVAVGVAFHYHLQRVFWT DTVQNKVFSVDINGLNIQEVLNVSVETPENLAVDWVNNKIYLVETKVNR IDMVNLDGSYRVTLITENLGHPRGIAVDPTVGYLFFSDWESLSGEPKLE RAFMDGSNRKDLVKTKLGWPAGVTLDMISKRVYWVDSRFDYIETVTYDG IQRKTVVHGGSLIPHPFGVSLFEGQVFFTDWTKMAVLKANKFTETNPQV YYQASLRPYGVTVYHSLRQPYATNPCKDNNGGCEQVCVLSHRTDNDGLG FRCKCTFGFQLDTDERHCIAVQNFLIFSSQVAIRGIPFTLSTQEDVMVP VSGNPSFFVGIDFDAQDSTIFFSDMSKHMIFKQKIDGTGREILAANRVE NVESLAFDWISKNLYWTDSHYKSISVMRLADKTRRTVVQYLNNPRSVVV HPFAGYLFFTDWFRPAKIMRAWSDGSHLLPVINTTLGWPNGLAIDWAAS RLYWVDAYFDKIEHSTFDGLDRRRLGHIEQMTHPFGLAIFGEHLFFTDW RLGAIIRVRKADGGEMTVIRSGIAYILHLKSYDVNIQTGSNACNQPTHP NGDCSHFCFPVPNFQRVCGCPYGMRLASNHLTCEGDPTNEPPTEQCGLF SFPCKNGRCVPNYYLCDGVDDCHDNSDEQLCGTLNNTCSSSAFTCGHGE CIPAHWRCDKRNDCVDGSDEHNCPTHAPASCLDTQYTCDNHQCISKNWV CDTDNDCGDGSDEKNCNSTETCQPSQFNCPNHRCIDLSFVCDGDKDCVD GSDEVGCVLNCTASQFKCASGDKCIGVTNRCDGVFDCSDNSDEAGCPTR PPGMCHSDEFQCQEDGICIPNFWECDGHPDCLYGSDEHNACVPKTCPSS YFHCDNGNCIHRAWLCDRDNDCGDMSDEKDCPTQPFRCPSWQWQCLGHN ICVNLSVVCDGIFDCPNGTDESPLCNGNSCSDFNGGCTHECVQEPFGAK CLCPLGFLLANDSKTCEDIDECDILGSCSQHCYNMRGSFRCSCDTGYML ESDGRTCKVTASESLLLLVASQNKIIADSVTSQVHNIYSLVENGSYIVA VDFDSISGRIFWSDATQGKTWSAFQNGTDRRVVFDSSIILTETIAIDWV GRNLYWTDYALETIEVSKIDGSHRTVLISKNLTNPRGLALDPRMNEHLL FWSDWGHHPRIERASMDGSMRTVIVQDKIFWPCGLTIDYPNRLLYFMDS YLDYMDFCDYNGHHRRQVIASDLIIRHPYALTLFEDSVYWTDRATRRVM RANKWHGGNQSVVMYNIQWPLGIVAVHPSKQPNSVNPCAFSRCSHLCLL SSQGPHFYSCVCPSGWSLSPDLLNCLRDDQPFLITVRQHIIFGISLNPE VKSNDAMVPIAGIQNGLDVEFDDAEQYIYWVENPGEIHRVKTDGTNRTV FASISMVGPSMNLALDWISRNLYSTNPRTQSIEVLTLHGDIRYRKTLIA NDGTALGVGFPIGITVDPARGKLYWSDQGTDSGVPAKIASANMDGTSVK TLFTGNLEHLECVTLDIEEQKLYWAVTGRGVIERGNVDGTDRMILVHQL SHPWGIAVHDSFLYYTDEQYEVIERVDKATGANKIVLRDNVPNLRGLQV YHRRNAAESSNGCSNNMNACQQICLPVPGGLFSCACATGFKLNPDNRSC SPYNSFIVVSMLSAIRGFSLELSDHSETMVPVAGQGRNALHVDVDVSSG FIYWCDFSSSVASDNAIRRIKPDGSSLMNIVTHGIGENGVRGIAVDWVA GNLYFTNAFVSETLIEVLRINTTYRRVLLKVTVDMPRHIVVDPKNRYLF WADYGQRPKIERSFLDCTNRTVLVSEGIVTPRGLAVDRSDGYVYWVDDS LDIIARIRINGENSEVIRYGSRYPTPYGITVFENSIIWVDRNLKKIFQA SKEPENTEPPTVIRDNINWLRDVTIFDKQVQPRSPAEVNNNPCLENNGG CSHLCFALPGLHTPKCDCAFGTLQSDGKNCAISTENFLIFALSNSLRSL HLDPENHSPPFQTINVERTVMSLDYDSVSDRIYFTQNLASGVGQISYAT LSSGIHTPTVIASGIGTADGIAFDWITRRIYYSDYLNQMINSMAEDGSN RTVIARVPKPRAIVLDPCQGYLYWADWDTHAKIERATLGGNFRVPIVNS SLVMPSGLTLDYEEDLLYWVDASLQRIERSTLTGVDREVIVNAAVHAFG LTLYGQYIYWTDLYTQRIYRANKYDGSGQIAMTTNLLSQPRGINTVVKN QKQQCNNPCEQFNGGCSHICAPGPNGAECQCPHEGNWYLANNRKHCIVD NGERCGASSFTCSNGRCISEEWKCDNDNDCGDGSDEMESVCALHTCSPT AFTCANGRCVQYSYRCDYYNDCGDGSDEAGCLFRDCNATTEFMCNNRRC IPREFICNGVDNCHDNNTSDEKNCPDRTCQSGYTKCHNSNICIPRVYLC DGDNDCGDNSDENPTYCTTHTCSSSEFQCASGRCIPQHWYCDQETDCFD ASDEPASCGHSERTCLADEFKCDGGRCIPSEWICDGDNDCGDMSDEDKR HQCQNQNCSDSEFLCVNDRPPDRRCIPQSWVCDGDVDCTDGYDENQNCT RRTCSENEFTCGYGLCIPKIFRCDRHNDCGDYSDERGCLYQTCQQNQFT CQNGRCISKTFVCDEDNDCGDGSDELMHLCHTPEPTCPPHEFKCDNGRC IEMMKLCNHLDDCLDNSDEKGCGINECHDPSISGCDHNCTDTLTSFYCS CRPGYKLMSDKRTCVDIDECTEMPFVCSQKCENVIGSYICKCAPGYLRE PDGKTCRQNSNIEPYLIFSNRYYLRNLTIDGYFYSLILEGLDNVVALDF DRVEKRLYWIDTQRQVIERMFLNKTNKETIINHRLPAAESLAVDWVSRK LYWLDARLDGLFVSDLNGGHRRMLAQHCVDANNTFCFDNPRGLALHPQY GYLYWADWGHRAYIGRVGMDGTNKSVIISTKLEWPNGITIDYTNDLLYW ADAHLGYIEYSDLEGHHRHTVYDGALPHPFAITIFEDTIYWTDWNTRTV EKGNKYDGSNRQTLVNTTHRPFDIHVYHPYRQPIVSNPCGTNNGGCSHL CLIKPGGKGFTCECPDDFRTLQLSGSTYCMPMCSSTQFLCANNEKCIPI WWKCDGQKDCSDGSDELALCPQRFCRLGQFQCSDGNCTSPQTLCNAHQN CPDGSDEDRLLCENHHCDSNEWQCANKRCIPESWQCDTFNDCEDNSDED SSHCASRTCRPGQFRCANGRCIPQAWKCDVDNDCGDHSDEPIEECMSSA HLCDNFTEFSCKTNYRCIPKWAVCNGVDDCRDNSDEQGCEERTCHPVGD FRCKNHHCIPLRWQCDGQNDCGDNSDEENCAPRECTESEFRCVNQQCIP SRWICDHYNDCGDNSDERDCEMRTCHPEYFQCTSGHCVHSELKCDGSAD CLDASDEADCPTRFPDGAYCQATMFECKNHVCIPPYWKCDGDDDCGDGS DEELHLCLDVPCNSPNRFRCDNNRCIYSHEVCNGVDDCGDGTDETEEHC RKPTPKPCTEYEYKCGNGHCIPHDNVCDDADDCGDWSDELGCNKGKERT CAENICEQNCTQLNEGGFICSCTAGFETNVFDRTSCLDINECEQFGTCP QHCRNTKGSYECVCADGFTSMSDRPGKRCAAEGSSPLLLLPDNVRIRKY NLSSERFSEYLQDEEYIQAVDYDWDPKDIGLSVVYYTVRGEGSRFGAIK RAYIPNFESGRNNLVQEVDLKLKYVMQPDGIAVDWVGRHIYWSDVKNKR IEVAKLDGRYRKWLISTDLDQPAAIAVNPKLGLMFWTDWGKEPKIESAW MNGEDRNILVFEDLGWPTGLSIDYLNNDRIYWSDFKEDVIETIKYDGTD RRVIAKEAMNPYSLDIFEDQLYWISKEKGEVWKQNKFGQGKKEKTLVVN PWLTQVRIFHQLRYNKSVPNLCKQICSHLCLLRPGGYSCACPQGSSFIE GSTTECDAAIELPINLPPPCRCMHGGNCYFDETDLPKCKCPSGYTGKYC EMAFSKGISPGTTAVAVLLTILLIVVIGALAIAGFFHYRRTGSLLPALP KLPSLSSLVKPSENGNGVTFRSGADLNMDIGVSGFGPETAIDRSMAMSE DFVMEMGKQPIIFENPMYSARDSAVKVVQPIQVTVSENVDNKNYGSPIN PSEIVPETNPTSPAADGTQVTKWNLFKRKSKQTTNFENPIYAQMENEQK ESVAATPPPSPSLPAKPKPPSRRDPTPTYSATEDTFKDTANLVKEDSE V.

As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a gene of interest for example a CD320 gene or an LRP2 gene, including mRNA that is a product of RNA processing of a primary transcription product.

As used herein, the term “strand comprising a sequence” refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature.

“G,” “C,” “A” and “U” each generally stand for a nucleotide that contains guanine, cytosine, adenine, and uracil as a base, respectively. “T” and “dT” are used interchangeably herein and refer to a deoxyribonucleotide wherein the nucleobase is thymine, e.g., deoxyribothymine, 2′-deoxythymidine or thymidine. However, it will be understood that the term “ribonucleotide” or “nucleotide” or “deoxyribonucleotide” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety. The skilled person is well aware that guanine, cytosine, adenine, and uracil may be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide comprising a nucleotide bearing such replacement moiety. For example, without limitation, a nucleotide comprising inosine as its base may base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine may be replaced in the nucleotide sequences of the invention by a nucleotide containing, for example, inosine. Sequences comprising such replacement moieties are embodiments of the invention.

The term “siRNA” refers to a compound, cocktail, composition or agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript via the RISC/AGO (RNA-induced silencing complex) complex, whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC/AGO complex, which has RNAse cleave activity, resulting in mRNA degradation and the protein encoded by the mRNA is not produced or is produced at a reduced level as compared to untreated cell. This causes the “knockdown” effect or reduced protein levels of the gene targeted by the siRNA compared to control treated cells. The siRNA modulates, e.g., inhibits, the expression of CD320 in a cell or LRP2 in a cell, e.g., a cell within a subject, such as a mammalian subject.

In one embodiment, an RNAi agent of the invention includes a single stranded RNA that interacts with a target RNA sequence, e.g., a CD320 or LRP2 target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory, it is believed that long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease-Ill-like enzyme, processes the dsRNA into 19-23 base pair (bp) short interfering RNAs with characteristic two base 3′ overhangs (Bernstein, et al., (2001) Nature 409:363). Initially, the siRNAs may consist of two RNA strands, an antisense (or guide) strand and a sense (or passenger) strand, which form a duplex that varies in length from 10-80 bp in length with or without a 3′ nucleotide overhang. A dsRNA can include one or more single-stranded overhang(s) of one or more nucleotides. In one embodiment, at least one end of the dsRNA has a single-stranded nucleotide overhang of 1 to 4, generally 1 or 2 nucleotides. In another embodiment, the antisense strand of the dsRNA has 1-10 nucleotide overhangs each at the 3′ end and the 5′ end over the sense strand. In further embodiments, the sense strand of the dsRNA has 1-10 nucleotide overhangs each at the 3′ end and the 5′ end over the antisense strand.

The siRNA are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense (guide) strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188). Thus, in one aspect the invention relates to a single stranded RNA (siRNA) generated within a cell and which promotes the formation of a RISC complex to effect silencing of the target gene, i.e., a CD320 or LRP2 gene. Accordingly, the term “siRNA” is also used herein to refer to an RNAi as described above.

In another embodiment, the RNAi agent may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target mRNA. Single-stranded RNAi agents bind to the RISC endonuclease Argonaute 2, which then cleaves the target mRNA. The single-stranded siRNAs are generally 15-80 nucleotides and may be chemically modified to improve metabolic stability and activity; wherein one or multiple pyrimidine nucleotides could be modified as 2′-deoxy-2′-fluoronucleotides, one or more purine nucleotides could be modified as 2′-deoxypurine nucleotides and, moreover, wherein terminal cap modifications could be present at the 3′ or 5′ ends; particularly by the introduction of one or more 2′-deoxythymidine nucleotides, or by the introduction of one or more phosphorothioate groups linking any nucleotides in the sequence but especially at the 3′ and 5′ end. In addition, a 3′-terminal phosphate or vinylphosphonate group could be introduced. Examples of such modifications would include but not be limited to modifications to the ribose moieties of the nucleotides such as: 2′-deoxy, 2′-deoxyfluoro, 2′-methoxy (2′-O-methyl) (Hutvanger et al., (2004) PLOS Biol 2, 0465-0475; Janas et al., (2019) Nuc Acid Res 47, 3306-3320; Jackson et al., (2006) RNA 12, 1197-1205), and 2′-methoxyethyl, wherein it is understood that the stereochemistry of the 2′-substituent could be in the ribo- or arabino-orientation. Another modification could be 2′-trifluoromethoxy. Other modifications to the ribose moieties could include bridging modifications such that the 2′-carbon of the sugar moiety is covalently linked to the 4′-carbon of the sugar moiety by a methylene or methoxymethylene group to afford bridged nucleotides described in the art as LNA and (S)-cET, respectively (Corey et al., (2018) Nuc Acid Res 46; 1584-1600). In addition, the sugar moiety could be modified by removal of the bond between carbons C2′ and C3′ to afford “open” chain nucleotides analogous to those described in WO 2011/139843 A2. The ribose moiety of the RNA nucleotides could also be replaced by a morpholino group to afford PMO nucleotides. Modifications to the phosphate diester moieties of the nucleotides are also possible and could include but not be limited to replacement of the phosphodiester group by phosphorothioate and thio-phosphoramidate (Eckstein et al., (2014) Nuc Acid Therapeutics 24, 374-387). The ends of the strand could be modified with 2′-deoxynucleotides such as dT and, further, the dT nucleotides could be modified by phosphorothioate groups in place of diphosphate esters. The design and testing of single-stranded siRNAs are described in U.S. Pat. No. 8,101,348 and in Lima et al., (2012) Cell 150: 883-894, the entire contents of each of which are hereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012) Cell 150; 883-894.

In another embodiment, an “RNAi” for use in the compositions, uses, and methods of the invention is a double-stranded RNA and is referred to herein as a “double stranded RNAi agent,” “double-stranded RNA (dsRNA) molecule,” “dsRNA agent,” or “dsRNA”. The term “dsRNA” refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having “sense” (passenger) and “antisense” (guide) orientations with respect to a target RNA, i.e., a CD320 gene or LRP2 gene. In some embodiments of the invention, a double-stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene-silencing mechanism referred to herein as RNA interference or RNAi.

In general, the majority of nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide and/or a modified nucleotide. In addition, as used in this specification, an “RNAi agent” may include ribonucleotides with chemical modifications (Corey et al., (2018) Nuc Acid Res 46; 1584-1600); an RNAi agent may include substantial modifications at multiple nucleotides or at a single nucleotide. Such modifications may include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by “RNAi agent” for the purposes of this specification and claims. Examples of such modifications would include but not be limited to modifications to the ribose moieties of the nucleotides such as: 2′-deoxy, 2′-deoxyfluoro, 2′-methoxy (2′-O-methyl) (Hutvanger et al., (2004) PLOS Biol 2, 0465-0475; Janas et al., (2019) Nuc Acid Res 47, 3306-3320; Jackson et al., (2006) RNA 12, 1197-1205), and 2′-methoxyethyl, wherein it is understood that the stereochemistry of the 2′-substituent could be in the ribo- or arabino-orientation. Another modification could be 2′-trifluoromethoxy. Other modifications to the ribose moieties could include bridging modifications such that the 2′-carbon of the sugar moiety is covalently linked to the 4′-carbon of the sugar moiety by a methylene or methoxymethylene group to afford bridged nucleotides described in the art as LNA and (S)-cET, respectively (Corey et al., (2018) Nuc Acid Res 46; 1584-1600). In addition, the sugar moiety could be modified by removal of the bond between carbons C2′ and C3′ to afford “open” chain nucleotides analogous to those described in WO 2011/139843 A2. The ribose moiety of the RNA nucleotides could also be replaced by a morpholino group to afford PMO nucleotides. Modifications to the phosphate diester moieties of the nucleotides are also possible and could include but not be limited to replacement of the phosphodiester group by phosphorothioate and thio-phosphoramidate (Eckstein et al., (2014) Nuc Acid Therapeutics 24, 374-387). The ends of the sense and antisense strands could be modified with 2′-deoxynucleotides such as dT and, further, the dT nucleotides could be modified by phosphorothioate groups in place of diphosphate esters (FIG. 19 ).

Chemical modifications to the ribonucleotides could be made at any individual or combination of nucleotides in the antisense and sense strands. In some cases, all the nucleotides in either the antisense or sense strand, or in both the antisense and sense strands are chemically modified (Allerson et al., (2005) J Med Chem 48, 901-904). In other cases, only some of the nucleotides in the antisense or sense strand, or in both the antisense and sense strands are chemically modified (Chiu et al., (2003) RNA 9, 1034-1048). In yet other cases, the modifications could follow a pattern of alternating 2′-methoxy and 2′-fluoro modifications to either or both strands of the siRNA and sometimes the complementary nucleotides of the antisense and sense strands could contain chemical modifications which are not identical, for example, where one member of a complementary nucleotide pair has a 2′-methoxy modification and the other member has a 2′-fluoro modification (Choung et al. (2006) Biochem Biophys Res Commun 342, 919-927; Hassler et al., (2018) Nucleic Acid Res 46, 2185-2196).

The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a “hairpin loop.” Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a “linker.” The RNA strands may have the same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the dsRNA minus any overhangs that are present in the duplex. In addition to the duplex structure, an RNAi agent may comprise one or more nucleotide overhangs.

In one embodiment, an RNAi agent of the invention is a dsRNA of 20-30 nucleotides that interacts with a target RNA sequence, e.g., a CD320 target mRNA sequence or a LRP2 target mRNA sequence, to direct the cleavage of the target RNA.

The term “antisense strand” refers to the strand of a double stranded RNAi agent which includes a region that is substantially complementary to a target sequence (e.g., a human CD320 mRNA or a LRP2 mRNA). As used herein, the term “region complementary to part of an mRNA encoding CD320 or LRP2” refers to a region on the antisense strand that is substantially complementary to part of a mRNA sequence that codes for either CD320 or LRP2. Where the region of complementarity is not fully complementary to the target sequence, the mismatches are most tolerated in the terminal regions and, if present, are generally in a terminal region or regions, e.g., within 6, 5, 4, 3, or 2 nucleotides of the 5′ and/or 3′ terminus. For example, substantially complementary can in certain embodiments mean that in a hybridized pair of nucleobase sequences, at least 85% but not all of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide.

The term “sense strand,” as used herein, refers to the strand of a dsRNA that includes a region that is substantially complementary to a region of the antisense strand.

As used herein, the term “cleavage region” refers to a region that is located immediately adjacent to the cleavage site. The cleavage site is the site on the target at which cleavage occurs. In some embodiments, the cleavage region comprises three bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage region comprises two bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage site specifically occurs at the site bound by nucleotides 10 and 11 of the antisense strand, and the cleavage region comprises nucleotides 11, 12 and 13.

As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions may include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50° C. or 70° C. for 12-16 hours followed by washing. Other conditions, such as physiologically relevant conditions as may be encountered inside an organism, can apply. For example, a complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., RNAi. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides.

Sequences can be “fully complementary” with respect to each when there is base-pairing of the nucleotides of the first nucleotide sequence with the nucleotides of the second nucleotide sequence over the entire length of the first and second nucleotide sequences. However, where a first sequence is referred to as “substantially complementary” with respect to a second sequence herein, the two sequences can be fully complementary, or they may form one or more, but generally not more than 4, 3 or 2 mismatched base pairs upon hybridization, while retaining the ability to hybridize under the conditions most relevant to their ultimate application. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, may yet be referred to as “fully complementary” for the purposes described herein.

“Complementary” sequences, as used herein, may also include, or be formed entirely from, non-Watson-Crick base pairs and/or base pairs formed from non-natural and modified nucleotides, in as far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs include, but are not limited to, G:U Wobble or Hoogstein base pairing.

The terms “complementary,” “fully complementary” and “substantially complementary” herein may be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between the antisense strand of a dsRNA and a target sequence, as will be understood from the context of their use.

As used herein, a polynucleotide that is “substantially complementary to at least part of” a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding CD320 or an mRNA encoding LRP2) including a 5′ UTR, an open reading frame (ORF), or a 3′ UTR. For example, a polynucleotide is complementary to at least a part of a CD320 mRNA or LRP2 mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding CD320 or LRP2.

The term “inhibiting,” as used herein, is used interchangeably with “reducing,” “silencing,” “downregulating,” “suppressing” and other similar terms, and includes any level of inhibition.

The phrase “inhibiting expression of a CD320,” “inhibiting expression of a LRP2” as used herein, includes inhibition of expression of any CD320 or LRP2 gene (such as the identified gene from, e.g., a mouse, a rat, a monkey, or a human) as well as variants, (e.g., naturally occurring variants), or mutants of the identified gene. Thus, the CD320 or LRP2 gene may be a wild-type CD320 or LRP2 gene, a mutant CD320 or LRP2 gene, or a transgenic CD320 or LRP2 gene in the context of a genetically manipulated cell, group of cells, or organism.

“Inhibiting expression of a CD320 gene” or “Inhibiting expression of a LRP2 gene” includes any level of inhibition of a CD320 gene or a LRP2 gene, e.g., at least partial suppression of the expression of a CD320 or LRP2 gene, such as an inhibition of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. In a preferred embodiment the inhibition is assessed by expressing the level of CD320 or LRP2 protein in treated cells as a percentage of the level of mRNA in control cells, using the following formula:

-   -   Normalized protein level for treated cells/Normalized protein         level for control cells. The control cells are the negative         control siRNA. Normalized means the protein level is normalized         to the level of a housekeeping protein.

The expression of a CD320 or LRP2 gene may be assessed based on the level of any variable associated with CD320 or LRP2 gene expression, e.g., CD320 or LRP2 mRNA level, CD320 or LRP2 protein level. Inhibition may be assessed by a decrease in an absolute or relative level of one or more of these variables compared with a control level. The control level may be any type of control level that is utilized in the art, e.g., a pre-dose baseline level, or a level determined from a similar subject, cell, or sample that is untreated or treated with a control (such as, e.g., buffer only control or inactive agent control).

Contacting a cell with a RNAi agent, either ds or ss as used herein, includes contacting a cell by any possible means whether in vivo or in vitro. Contacting a cell with a RNAi agent includes contacting a cell in vitro with the RNAi agent or contacting a cell in vivo with the RNAi agent. The contacting may be done directly or indirectly. Thus, for example, the RNAi agent may be put into physical contact with the cell by the individual performing the method, or alternatively, the RNAi agent may be put into a situation that will permit or cause it to subsequently come into contact with the cell.

A “patient” or “subject,” as used herein, is intended to include either a human or non-human animal, preferably a mammal, e.g., a monkey. Most preferably, the subject or patient is a human.

A “CD320-associated disease,” as used herein, is intended to include any disease associated with a perturbation of the CD320 gene, or protein, polymorphisms, single nucleotide polymorphisms (SNPs) as well as epigenetic modifications of the CD320 gene. Such a disease may be caused, for example, by excess production of the CD320 protein, by CD320 gene mutations, by abnormal cleavage of the CD320 protein, by abnormal folding of the CD320 protein, by abnormal interactions between CD320 itself or with other proteins or other endogenous or exogenous substances. For example, cancer may be a CD320-associated disease. The degree of inhibition of protein expression may be measured by western blotting.

A “LRP2-associated disease,” as used herein, is intended to include any disease associated with a perturbation of the LRP2 gene, protein, polymorphisms, SNPs as well as epigenetic modifications of the CD320 gene. Such a disease may be caused, for example, by excess production of the LRP2 protein, by LRP2 gene mutations, by abnormal cleavage of the LRP2 protein, by abnormal folding of the LRP2 protein, by abnormal interactions between LRP2 molecules and other proteins or other endogenous or exogenous substances. For example, cancer may be a LRP2-associated disease. The degree of inhibition of protein expression may be measured by western blotting.

“Therapeutically effective amount,” as used herein, is intended to include the amount of an RNAi agent that, when administered to a cell or a patient for treating a CD320 associated disease or a LRP2 associated disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating or maintaining the existing disease or one or more symptoms of disease or by preferentially causing the death of a disease cell as compared to a non-disease cell). The “therapeutically effective amount” may vary depending on the RNAi agent, how the agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, stage of pathological processes mediated by CD320 or LRP2 expression, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated.

“Prophylactically effective amount,” as used herein, is intended to include the amount of an RNAi agent that, when administered to a subject who does not yet experience or display symptoms of a CD320 associated disease or a LRP2 associated disease, but who may be predisposed to the disease, is sufficient to prevent or ameliorate the disease or one or more symptoms of the disease. Ameliorating the disease includes slowing the course of the disease or reducing the severity of later-developing disease. The “prophylactically effective amount” may vary depending on the RNAi agent, how the agent is administered, the degree of risk of disease, and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated.

A “therapeutically-effective amount” or “prophylactically effective amount” also includes an amount of an RNAi agent that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. RNAi agents employed in the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment.

Pharmaceutical Compositions

The methods described herein include administration of a LRP2 inhibiting composition and/or a CD320 inhibiting composition, e.g., a first siRNA targeting a CD320 gene and/or a second siRNA targeting a LRP2 gene. In some embodiments, the LRP2 inhibiting composition and/or the CD320 inhibiting composition is a pharmaceutical composition.

The methods described herein also include administration of one or multiple LRP2 inhibiting compositions and/or one or multiple CD320 inhibiting compositions, e.g., one or more siRNAs targeting a CD320 gene and/or one or more siRNAs targeting an LRP2 gene. It is understood that such compositions could be chemically modified in a variety of ways and that such modifications need not be identical in compositional mixtures. In some embodiments, the LRP2 inhibiting composition and/or the CD320 inhibiting composition is a pharmaceutical composition.

The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical, pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intraparenchymal, intrathecal or intraventricular, administration.

The compositions can be delivered in a manner to target a particular tissue, such as the lung cells or breast cells or brain cells or bladder cells or uterine cells or cervix cells or prostate cells. Pharmaceutical compositions can be delivered by injection directly into the brain. The injection can be by stereotactic injection into a particular region of the brain (e.g., the substantia nigra, cortex, hippocampus, striatum, or globus pallidus), or the dsRNA can be delivered into multiple regions of the central nervous system (e.g., into multiple regions of the brain, and/or into the spinal cord). The dsRNA can also be delivered into diffuse regions of the brain (e.g., diffuse delivery to the cortex of the brain). In general siRNAs are administered 1) by intratumoral injection, 2) by systemic injection, 3) by slow release from an implanted polymer. Other tissue specificity could be achieved by antibody or small molecule conjugation, or by a tissue-specific delivery device (e.g., a catheter can be used to deliver to the bladder).

In one embodiment, an RNAi targeting either LRP2 or the CD320 can be delivered by way of a cannula or other delivery device having one end implanted in a tissue. The cannula can be connected to a reservoir of the RNAi composition. The flow or delivery can be mediated by a pump, e.g., an osmotic pump or minipump. In one embodiment, a pump and reservoir are implanted in an area distant from the tissue, e.g., in the abdomen, and delivery is affected by a conduit leading from the pump or reservoir to the site of release.

Accordingly, in some embodiments, the pharmaceutical compositions described herein comprise one or more pharmaceutically acceptable excipients. The pharmaceutical compositions described herein are formulated for administration to a subject.

As used herein, a pharmaceutical composition or medicament includes a pharmacologically effective amount of at least one of the described RNAi agents and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients (excipients) are substances other than the Active Pharmaceutical Ingredient (API, therapeutic product, e.g., CD320 RNAi agent or LRP2 RNAi agent) that are intentionally included in the drug delivery system. Excipients do not exert or are not intended to exert a therapeutic effect at the intended dosage. Excipients can act to a) aid in processing of the drug delivery system during manufacture, b) protect, support, or enhance stability, bioavailability or patient acceptability of the API, c) assist in product identification, and/or d) enhance any other attribute of the overall safety, effectiveness, of delivery of the API during storage or use. A pharmaceutically acceptable excipient may or may not be an inert substance.

Excipients include, but are not limited to: absorption enhancers, anti-adherents, anti-foaming agents, anti-oxidants, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, delivery polymers, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavors, glidants, humectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repelling agents, and wetting agents.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor.RTM. ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The composition, understood to include formulations and drug delivery systems, should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.

The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

Dosage and Timing

The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments. Estimates of effective dosages and in vivo half-lives for the LRP2 inhibiting composition and or the CD320-inhibiting compositions encompassed by the invention can be made using conventional methodologies or on the basis of in vivo testing using an appropriate animal model, as described elsewhere herein.

In general, a suitable dose of a pharmaceutical composition of the LRP2 inhibiting composition and/or the CD320-inhibiting composition will be in the range of 0.01 to 300.0 milligrams per kilogram body weight of the recipient per day, generally in the range of 1 to 50 mg per kilogram body weight per day.

For example, the LRP2 inhibiting composition and/or the CD320-inhibiting composition can be an siRNA composition of one or more siRNAs, and can be administered at, 0.01 mg/kg, 0.05 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.628 mg/kg, 2 mg/kg, 3 mg/kg, 5.0 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, 400 mg/kg per single dose. In another embodiment, the dosage is between 0.15 mg/kg and 0.3 mg/kg. For example, the LRP2 and/or the CD320-inhibiting composition can be administered at a dose of 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, or 0.3 mg/kg. In an embodiment, the LRP2 and/or the CD320-inhibiting composition is administered at a dose of 0.3 mg/kg.

The pharmaceutical composition may be administered once daily, or once or twice every 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. The dosage unit can be compounded for delivery over several days, e.g., using a conventional sustained release formulation which provides sustained release of the LRP2 inhibiting composition and/or the CD320-inhibiting composition over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the present invention.

In an embodiment, the LRP2-inhibiting composition and/or the CD320-inhibiting composition is dependent upon the tumor cell line, and the dosage is 0.3 mg/kg, and wherein the dose is administered once every 21 days. In another embodiment, the effective amount is 0.3 mg/kg and the effective amount is administered once every 21 days via a 70 minute infusion of 1 mL/min for 15 minutes followed by 3 mL/min for 55 minutes. In another embodiment, the effective amount is 0.3 mg/kg and the effective amount is administered at two doses every 21-28 days via a 60 minute infusion of 3.3 mL/min, or via a 70 minute infusion of 1.1 mL/min for 15 minutes followed by 3.3 mL/min for 55 minutes

A dosage of a LRP2-inhibiting composition and/or the CD320-inhibiting composition can be adjusted for treatment

A LRP2-inhibiting composition and/or the CD320-inhibiting composition can be administered in combination with other known agents effective in treatment of pathological processes mediated by target gene expression.

In another embodiment, the pharmaceutical composition is formulated for administration according to a dosage regimen described herein, e.g., not more than once every four weeks, not more than once every three weeks, not more than once every two weeks, or not more than once every week. In another embodiment, the administration of the pharmaceutical composition can be maintained for a month or longer, e.g., one, two, three, or six months, or one year or longer.

In embodiments of the pharmaceutical compositions described herein, the RNAi (e.g., dsRNA) is administered with a buffer solution. In embodiments, the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof. In embodiments, the buffer solution is phosphate buffered saline (PBS).

In embodiments of the pharmaceutical compositions described herein, the composition is administered intravenously.

In embodiments of the pharmaceutical compositions described herein, the composition is administered subcutaneously.

In certain embodiments, a pharmaceutical composition, e.g., a composition described herein, includes a lipid formulation. In embodiments, the composition is administered intravenously.

In some embodiments, a pharmaceutical composition, e.g., a composition described herein, includes a cationic polyamine formulation or nanoparticle (e.g., JetPEI). In some embodiments, the composition is administered intravenously.

In another embodiment, the pharmaceutical composition is formulated for administration according to a dosage regimen described herein, e.g., not more than once every four weeks, not more than once every three weeks, not more than once every two weeks, or not more than once every week. In another embodiment, the administration of the pharmaceutical composition can be maintained for a month or longer, e.g., one, two, three, or six months, or one year or longer.

In another embodiment, a composition containing an RNAi agent featured in the invention, e.g., a dsRNA targeting LRP2 or CD320, is administered with a non-RNAi therapeutic agent, such as an agent known to treat a cancer such as lung cancer. In another embodiment, a composition containing an RNAi agent featured in the invention, e.g., a dsRNA targeting LRP2 and/or CD320, is administered along with a non-RNAi therapeutic regimen, such as radiation, chemotherapy, immunotherapy, photodynamic therapy or a combination thereof.

In an aspect provided herein is a method of inhibiting LRP2 and/or CD320 expression in a cell, the method comprising: (a) introducing into the cell an RNAi agent (e.g., a dsRNA) described herein and (b) maintaining the cell of step (a) fora time sufficient to obtain degradation of the mRNA transcript of an LRP2 gene and/or CD320 gene, thereby inhibiting expression of the LRP2 gene and/or CD320 gene in the cell.

In an aspect provided herein is a method for reducing or inhibiting the expression of LRP2 gene and/or CD320 genes in a cell. The method includes: (a) introducing into the cell one or more complimentary double-stranded ribonucleic acid (dsRNA) molecules, in which one sequence is designated the sense strand and the other sequence the anti-sense strand, and wherein the anti-sense strand has significant complementarity to a portion of mRNA encoding for LRP2 or CD320. The complimentary region is 15-30 nucleotides in length, and generally 19-24 nucleotides in length, and the dsRNA, upon entering a cell expressing LRP2 and/or CD320, inhibits the expression of the LRP2 protein and/or CD320 protein by at least 10%, e.g., at least 20%, at least 30%, at least 40% or more; (b) single or repeated treatment of the cell with dsRNAs, as described in part (a), so as to maintain the inhibition of LRP2 and/or CD320 protein expression over a desired period of time by at least 10%, e.g., at least 20%, at least 30%, at least 40% or more.

In embodiments of the foregoing methods of inhibiting LRP2 and/or CD320 expression in a cell, the cell is treated ex vivo, in vitro, or in vivo. In embodiments, the cell is a melanoma, glioblastoma, lung carcinoma, triple negative breast carcinoma, renal carcinoma, pancreatic carcinoma, hepatocellular carcinoma, ovarian carcinoma and prostate carcinoma.

In some embodiments, the cell is present in a subject in need of treatment, prevention and/or management of a CD320-associated disease or a LRP2-associated disease.

In embodiments, the expression of LRP2 and/or CD320 is inhibited by at least 30%.

In embodiments, the RNAi (e.g., dsRNA) has an IC₅₀ in the range of 0.01-50 nM.

In embodiments, the RNAi (e.g., dsRNA) has an IC₅₀ in the range of 0.01-1 nM.

In certain embodiments, the cell is a mammalian cell (e.g., a human, non-human primate, or rodent cell).

In one embodiment, the cell is treated ex vivo, in vitro, or in vivo (e.g., the cell is present in a subject (e.g., a patient in need of treatment, prevention and/or management of a disorder related to LRP2 and/or CD320 expression).

In one embodiment, the subject is a mammal (e.g., a human) at risk, or diagnosed with a proliferation disorder.

In embodiments, the RNAi (e.g., dsRNA) is formulated as an lipid nanoparticle (LNP) polyplex (polyamine) formulation.

In embodiments, RNAi (e.g., dsRNA) is administered at a dose of 0.05001-500.01 mg/kg.

In embodiments, the RNAi (e.g., dsRNA) is administered at a concentration of 0.01 mg/kg-50.1 mg/kg bodyweight of the subject.

In embodiments, the RNAi (e.g., dsRNA) is formulated as an LNP formulation and is administered at a dose of 0.050.1-50.5 mg/kg.

In embodiments, the RNAi (e.g., dsRNA) has an IC₅₀ in the range of 0.01-10 nM.

In embodiments, the RNAi (e.g., dsRNA) or composition comprising the RNAi is administered according to a dosing regimen. In embodiments, the RNAi (e.g., dsRNA) or composition comprising the RNAi is administered as a single dose or at multiple doses, e.g., according to a dosing regimen.

The term “sample,” as used herein, includes a collection of fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum and serosal fluids, plasma, cerebrospinal fluid, ocular fluids, lymph, urine, saliva, and the like. Tissue samples may include samples from tissues, organs or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from a tumor. In preferred embodiments, a “sample derived from a subject” refers to blood or plasma drawn from the subject. In further embodiments, a “sample derived from a subject” refers to tissue biopsy derived from the subject.

In one embodiment, an RNAi (e.g., a dsRNA) featured herein includes a first sequence of a dsRNA that is selected from the group consisting of the sense sequences of Table 1 and a second sequence that is selected from the group consisting of the corresponding antisense sequences of Table 1. It is understood that the suffix A (e.g., OSC17A) represents the antisense strand whereas the suffix S (e.g., OSC17S) represents the sense strand. In those instances when we refer to an siRNA with no suffix (e.g., OSC17), we mean that to indicate the dsRNA comprised of the antisense and sense strands corresponding to that number (e.g., OSC17A paired with OSC17S).

In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting CD320, upon contact with a cell expressing CD320, inhibits the expression of a CD320 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting CD320 is formulated in a stable nucleic acid lipid particle (SNALP).

In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting LRP2, upon contact with a cell expressing LRP2, inhibits the expression of a LRP2 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting LRP2 is formulated in a stable nucleic acid lipid particle (SNALP).

In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting CD320, upon contact with a cell expressing CD320, inhibits the expression of a CD320 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting CD320 is formulated as a complex, which may exist as a nanoparticle, with a cationic polyamine.

In some embodiments the RNAi is from about 15 to about 25 nucleotides in length, and in other embodiments the RNAi is from about 25 to about 30 nucleotides in length. An RNAi targeting LRP2, upon contact with a cell expressing LRP2, inhibits the expression of a LRP2 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35% or at least 40% or more, such as when assayed by a method as described herein. In one embodiment, the RNAi targeting LRP2 is formulated as a complex, which may exist as a nanoparticle, with a cationic polyamine.

Referring now to Table 1—DNA sequences are illustrated, which are subsequently transcribed into shRNA, which hence targets the CD320 or LRP2 mRNA for destruction in the cell. shRNA sequences used in lentiviral vectors illustrates the sequences that were used to target the CD320 sequence coding for the CD320 protein and the LRP2 sequence coding for the LRP2 protein. The Each vector that carried a shRNA coding sequence also contained a unique drug resistance gene which would allow for selecting those cells that had taken up the shRNA as those cells that had not taken up the shRNA having the unique drug resistance gene would not survive. On day 2, drug selection was started. On day 3, the cells were harvested and plated in a new dish. Only the cells with a drug resistance gene, i.e., those cells that had taken up shRNA virus particles would survive this re-plating procedure. From day 4 on, each culture was closely observed for cell growth. The cells that were infected with the irrelevant control shRNA kept on growing as expected (since the shRNA was essentially a non-functional shRNA)—data not shown. The results for the cell lines that took up the CD320+LRP2 shRNAs are shown in Table 1.

TABLE 1 Anti-Sense  Location Name Target Sense Sequence Sequence in DNA shScramble non-targeting  CCTAAGGTTAAGTC CGAGGGCGACTTAAC N/A control GCCCTCG(SEQ ID CTTAGG(SEQ ID   NO. 941) NO. 942) shCD320-  CD320  CCCTCAGAGACCTG AAGAGCTCAGGTCTC 1006- #27 (NM_016579.3) AGCTCTT(SEQ ID TGAGGG(SEQ ID   1026 NO. 943) NO. 944) shLRP2-  LRP2  CCTGTAATAAACAC AAGAGTAGTGTTTAT 2800- #89 (NM_004525.2) TACTCTT(SEQ ID TACAGG(SEQ ID 2820 NO. 945) NO. 946) The preliminary studies show that cancer cells are selectively killed by CD320 and LRP2 knockdown, while normal cells remain unaffected (Table 2).

Table 2 shows the effect of simultaneous knockdown of CD320 and LRP2 on cell viability.

TABLE 2 Outcome of CD320/LRP2 knockdown Cell arrest/death Alive Cancer (Lung) HCC15 ✓ H157 ✓ H358 ✓ H1999 ✓ Non-cancer Normal fibroblast ✓ LDLR mutant fibroblast ✓

Additional cancer cell lines were also treated with the compounds described herein to determine whether cancer cell lines were more susceptible to growth inhibition and toxicity as compared to non-cancer cells of the same origin. Cell lines from skin, prostate, and brain cancers were screened similarly to the experimental outline in FIG. 1 . Table 3 summarizes the effects of simultaneous knockdown of CD320 and LRP2 in cancer and normal cells.

TABLE 3 shCD320 + Cell shSCR shCD320 shLRP2 shLRP2 Comments Normal cells GM05659 +++ +++ +++ +++ no effect of knockdown GM00701 +++ ++ +++ +++ cells grow very slow; hard to determine if any affect of knockdown SAEC pending Lung cells HCC15 +++ + + + cells strongly affected by knockdown H157 +++ + ++ + senescent phenotype H358 +++ ++ ++ ++ morphology changes; cells rounded H1993 +++ ++ ++ + cells rounded; morphology change Melanoma Cells MDA-MB-4353 +++ ++ + + morphology change; cells strongly affected by double knockdown Prostate cells LncAP +++ ++ ++ + cells rounded; morphology change PC3 +++ +++ ++ +++ cells minimally to not affected by knockdown DU-145 +++ ++ + ++ cells modestly affected by knockdown Glioblastoma A172 +++ + + 0 cells strongly affected by knockdown U251MG +++ + ++ 0 cells strongly affected by knockdown U343 +++ +++ ++ +++ cells modestly affected by LRP2 knockdown T98G +++ +++ ++ ++ cells slightly affected by knockdown +++ cells unaffected compared to shSCR (control) ++ cells modestly affected compared to shSCR (control) + cells significantly affected compared to shSCR (control) 0 vast majority of cells killed compared to shSCR (control)

The screening results showed that lung, prostate, skin, and brain cancer cell lines were growth-inhibited or killed by the simultaneous knockdown (“double knockdown”) of CD320 and LRP2, while non-cancerous cells were unaffected.

Referring now to FIG. 2 , representative pictures of the cells were taken to record their phenotypes after the double knockdown of CD320 and LRP2 and to illustrate the sensitivity of cancer cell lines to knockdown of the expression of CD320 and LRP2 proteins.

Normal cells (GM05659 fibroblasts) or cancer cells were infected with lentiviruses expressing shRNAs to control sequences or to shCD320 and shLRP2 as described in FIG. 1 . The cells were grown as described in FIG. 1 . On the ninth day after transfection with the lentiviruses, pictures of the cells were taken. The solid line ovals indicate healthy growth of normal fibroblast infected with shRNAs to CD320 and LRP2. The broken line ovals indicate unhealthy dying cells of cancer cell lines infected with shRNAs to CD320 and LRP2.

These results support use of the compounds as therapeutics based upon decreasing expression of CD320 and LRP2 protein preferentially resulting in detrimental effects in cancer cells as compared to non-cancer cells. The original experiments were conducted using shRNAs delivered by lentiviral vectors. Short inhibitory RNAs (siRNAs), having a sequence complimentary to a portion of the CD320 protein and/or the LRP2 protein were designed. The siRNAs can be chemically modified to increase their stability and potency and reduce their immunogenicity, and multiple platforms exist for their delivery in clinical applications.

siRNA sequences that efficiently knock down the protein levels of LRP2 and/or CD320 were designed and identified. Table 4 is a list of siRNA sequences complementary to mRNA for CD320 or LRP2 that were tested for their ability to knock down CD320 or LRP2 protein, respectively (see FIG. 3 , FIG. 4 , FIG. 5 , FIG. 12 , and FIG. 15 ).

TABLE 4 Nucleo- tide Passenger  start  ID Sequence Target Size site Location OSS1 CCUAAGGUU none 21 N/A N/A AAGUCGCCC UCG  (SEQ ID  NO. 947) OSS2 UGGUUUACA none 19 N/A N/A UGUUGUGUG A (SEQ ID  NO. 948) OSL231 GGGCUCUAG LRP2 25 12537 CDS GUUUGGUGC UAUCAAA  (SEQ ID  NO. 949) NM_004525.2 OSL245 GGACUGAUA LRP2 25 12995 CDS GGAGAGUCA UUGCAAA  (SEQ ID  NO. 950) NM_004525.2 OSL47 CCUGUAAUA LRP2 21  2800 CDS AACACUACU CUU  (SEQ ID  NO. 951) NM_004525.2 OSL104 CCUUCUAUG LRP2 21  5677 CDS AACCUGGCC UUA (SEQ ID  NO. 952) NM_004525.2 OSL90 GUGAUUUGA LRP2 19  5126 CDS UUAUACGGC A (SEQ ID  NO. 953) NM_004525.2 OSL119 CCUCAAAUG LRP2 19  6266 CDS GCUGUAGCA A (SEQ ID  NO. 954) NM_004525.2 OSC17 GAACUGACA CD320 25   422 CDS AGAAACUGC GCAACUG (SEQ ID  NO. 955) NM_016579.3 OSC47 CCCUCAGAG CD320 21  1006 3′-UTR ACCUGAGCU CUU (SEQ ID  NO. 956) NM_016579.3

The list of all potential siRNA sequences is quite large. We have identified 340 potential siRNA sequences to LRP2 and 59 potential siRNA sequences to CD320. (See Table 5 and Table 6 for the complete list and Table 5A and Table 6A identify the target position and sequence that is complementary for each antisense sequence identified). In addition, chemical modifications can be made to these siRNA sequences to improve their stability and reduce their off-target effects. siRNA molecules are vulnerable to metabolic degradation, for example by RNase or DNase enzymes. Chemical modification of siRNA molecules by incorporation of one or more unnatural, that is, manmade, nucleotides within the sequence can render siRNAs resistant to such metabolic degradation and increase their biological half-life in the cell or in plasma. Moreover, the inclusion of manmade nucleotides at strategic locations within the siRNA sequence can decrease the immunogenicity of the siRNA and improve the selectivity for the guide strand over the passenger strand. Modified siRNA molecules may incorporate manmade nucleotides of a single type or may include multiple manmade nucleotides of different types. Manmade nucleotides may include, but are not limited to, those which contain chemical modifications to the ribose moiety or to the phosphate moieties (FIG. 19 and Table 7). Examples of manmade nucleotides include, but are not limited to, the structures shown in the Table 7. Moreover, modification of multiple structural elements may be combined. In addition, modification may be made to the nucleobase B, which, in addition to the natural RNA nucleobases (G, C, A, U), may include unnatural bases, such as those containing a sulfur atom (e.g., thiouracil).

TABLE 7 Nucleotide modifications corresponding to FIG. 19A B Designation^(a) Y X Z R R′ (nucleobase) [2fN] O O O F H G, C, A, U, other 2′-FANA O O O H F G, C, A, U, other [mN] O O O OMe H G, C, A, U, other 2′-MOE O O O CH₂CH₂OMe H G, C, A, U, other 2′-EA O O O CH₂CH₂NH₂ H G, C, A, U, other 2′-DMEA O O O CH₂CH₂NMe₂ H G, C, A, U, other 2′-DMAP O O O CH₂CH₂CH₂NMe₂ H G, C, A, U, other * as in N1*N2 O S O OH H G, C, A, U, other ** as in N1**N2 S S O OH H G, C, A, U, other 2′-deoxy O O O H H G, C, A, U, other 4′-S O O S H H G, C, A, U, other F-SRNA O O S F H G, C, A, U, other Me-SRNA O O S OMe H G, C, A, U, other 4′-S-FANA O O S H F G, C, A, U, other ^(a)N designates an arbitrary ribonucleotide or deoxyribonucleotide or analogs thereof. In some embodiments, chemical modification is made to the phosphodiester group which covalently connects two nucleotides, such that, for example, one or two oxygen atoms in that group are substituted with sulfur atoms, as indicated by a single or double asterisk between two nucleotides to represent the replacement of one or two oxygen atoms with sulfur in the phosphodiester (Table 7 and FIG. 19A). In some embodiments, the siRNA sequences may include other manmade nucleotides wherein further structural modifications have been made to the ribose moiety, such as the addition of bridging atoms that covalently link carbons 2′ and 5′ of the ribose moiety (FIG. 19B-C) or positions 1′ and 2′ of the ribose moiety (FIG. 19D), or alternatively, changes to the size of the sugar ring in a given nucleotide, for example, deletion of the bond between carbons 2′ and 3′ of the ribose moiety (FIG. 19E), or increasing the size of the sugar ring from five to six atoms (FIG. 19F-G).

TABLE 5 CD320 OS ID Antisense Strand (5′ TO 3′)  OSID Sense Strand (5′ TO 3′)  OSC1A UCUUAUCCCUGCGCACGCGCA[dT][dT]  OSC1S UGCGCGUGCGCAGGGAUAAGA[dT][dT] (SEQ ID NO 1) (SEQ ID NO: 94) OSC2A UCUCUUAUCCCUGCGCACGCG[dT][dT](SEQ  OSC2S CGCGUGCGCAGGGAUAAGAGA[dT][dT] ID NO 2) (SEQ ID NO: 95) OSC3A AUGCUGUCCCCACAGCGGCGC[dT][dT](SEQ  OSC3S GCGCCGCUGUGGGGACAGCAU[dT][dT] ID NO 3) (SEQ ID NO: 96) OSC4A AUCCAACCGCCGCUCAUGCUG[dT][dT](SEQ  OSC4S CAGCAUGAGCGGCGGUUGGAU[dT][dT] ID NO 4) (SEQ ID NO: 97) OSC5A UGGAAAGCGGGCUCGCGGCGG[dT][dT](SEQ  OSC5S CCGCCGCGAGCCCGCUUUCCA[dT][dT] ID NO 5) (SEQ ID NO: 98) OSC6A AACUUGGUGGGUGGGCACGAG[dT][dT](SEQ  OSC6S CUCGUGCCCACCCACCAAGUU[dT][dT] ID NO 6) (SEQ ID NO: 99) OSC7A UGGAACUUGGUGGGUGGGCAC[dT][dT](SEQ  OSC7S GUGCCCACCCACCAAGUUCCA[dT][dT] ID NO 7) (SEQ ID NO: 100) OSC8A ACUGGAACUUGGUGGGUGGGC[dT][dT](SEQ  OSC8S GCCCACCCACCAAGUUCCAGU[dT][dT] ID NO 8) (SEQ ID NO: 101) OSC9A UAAGCCACUGGUGCGGCACUG[dT][dT](SEQ  OSC9S CAGUGCCGCACCAGUGGCUUA[dT][dT] ID NO 9) (SEQ ID NO: 102) OSC10A ACGCAUAAGCCACUGGUGCGG[dT][dT](SEQ  OSC10S CCGCACCAGUGGCUUAUGCGU[dT][dT] ID NO 10) (SEQ ID NO: 103) OSC11A UCCAAGUCCCUGUCGCAGCGC[dT][dT](SEQ  OSC11S GCGCUGCGACAGGGACUUGGA[dT][dT] ID NO 11) (SEQ ID NO: 104) OSC12A UCCUCAUCGCUGCCAUCGCUG[dT][dT](SEQ  OSC12S CAGCGAUGGCAGCGAUGAGGA[dT][dT] ID NO 12) (SEQ ID NO: 105) OSC13A UCACUGACGCCGGUGCAGGGG[dT][dT](SEQ  OSC13S CCCCUGCACCGGCGUCAGUGA[dT][dT] ID NO 13) (SEQ ID NO: 106) OSC14A UUGUCAGUUCCCCCAGAGCAG[dT][dT](SEQ  OSC14S CUGCUCUGGGGGAACUGACAA[dT][dT] ID NO 14) (SEQ ID NO: 107) OSC15A UUCUUGUCAGUUCCCCCAGAG[dT][dT](SEQ  OSC15S CUCUGGGGGAACUGACAAGAA[dT][dT] ID NO 15) (SEQ ID NO: 108) OSC16A AGUUUCUUGUCAGUUCCCCCA[dT][dT](SEQ  OSC16S UGGGGGAACUGACAAGAAACU[dT][dT] ID NO 16) (SEQ ID NO: 109) OSC17A- CAGUUGCGCAGUUUCUUGUCAGUUC[dT][dT] OSC17S- GAACUGACAAGAAACUGCGCAACUG 1 (SEQ ID NO 17) 1 [dT][dT](SEQ ID NO: 110) OSC17A- CAGUUGCGCAGUUUCUUGUCAGUUC[dT]*[dT] OSC17S- GAACUGACAAGAAACUGCGCAACUG[dT]* 2 (SEQ ID NO 18) 2 [dT](SEQ ID NO: 111) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] OSC17S- [mG][mA][mA][mC][mU][mG][mA][mC] 3 [mA][mG][mU][mU][mU][mC][mU][mU][mG]  3 [mA][mA][mG][mA][mA][mA][mC][mU][mG]  [mU][mC][mA][mG][mU][mU][mC][dT]*[dT]] [mC][mG][mC][mA][mA][mC][mU][mG] (SEQ ID NO 19)  [dT]*[dT](SEQ ID NO: 112)  OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] OSC17S- [mG][mA][mA][mC][mU][mG][mA][mC] 4 [mA][mG][mU][mU][mU][mC][mU][mU][mG] 4 [mA][mA][mG][mA][mA][mA][mC][mU][mG] [mU][mC][mA][mG][mU][mU][mC][dT]*[dT]] [mC][mG][mC][mA][mA][mC][mU][mG] (SEQ ID NO 20)  (SEQ ID NO: 113) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] OSC17S- [mG][mA][mA][mC][mU][mG][mA][mC] 5 [mA][mG][mU][mU][mU][mC][mU][mU][mG]  5 [mA][mA][mG][mA][mA][mA][mC][mU][mG] [mU][mC][mA][mG][mU][mU][mC]](SEQ ID  [mC][mG][mC][mA][mA][mC][mU][mG] NO 21) [dT]*[dT](SEQ ID NO: 114)  OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] OSC17S- [mG][mA][mA][mC][mU][mG][mA][mC] [mA][mG][mU][mU][mU][mC][mU][mU][mG]  6 [mA][mA][mG][mA][mA][mA][mC][mU][mG] [mU][mC][mA][mG][mU][mU][mC]](SEQ ID [mC][mG][mC][mA][mA][mC][mU][mG] 6 NO 22) (SEQ ID NO: 115) OSC17A- [mC][mA][mG][mU][mU][mG][mC][mG][mC] OSC17S- GAACUGACAAGAAACUGCGCAACUG[dT]*[dT] 7 [mA][mG][mU][mU][mU][mC][mU][mU][mG] 7 (SEQ ID NO: 116) [mU][mC][mA][mG][mU][mU][mC][dT]*[dT]] (SEQ ID NO 23) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] OSC17S- [2fG][mA][2fA][mC][2fU][mG][2fA][mC] 8 [2fA][mG][2fU][mU][2fU][mC][2fU][mU] 8 [2fA][mA][2fG][mA][2fA][mA][2fC][mU] [2fG][mU][2fC][mA][2fG][mU][2fU][mC][dT]* [2fG][mC][2fG][mC][2fA][mA][2fC][mU] [dT](SEQ ID NO 24) [2fG][dT]*[dT](SEQ ID NO: 117) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] OSC17S- [2fG][mA][2fA][mC][2fU][mG][2fA][mC] 9 [2fA][mG][2fU][mU][2fU][mC][2fU][mU][2fG] 9 [2fA][mA][2fG][mA][2fA][mA][2fC][mU] [mU][2fC][mA][2fG][mU][2fU][mC](SEQ ID [2fG][mC][2fG][mC][2fA][mA][2fC][mU] NO 25) [2fG][dT]*[dT](SEQ ID NO: 118) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] OSC17S- [2fG][mA][2fA][mC][2fU][mG][2fA][mC] 10 [2fA][mG][2fU][mU][2fU][mC][2fU][mU][2fG] 10 [2fA][mA][2fG][mA][2fA][mA][2fC][mU] [mU][2fC][mA][2fG][mU][2fU][mC][dT]*[dT] [2fG][mC][2fG][mC][2fA][mA][2fC][mU] (SEQ ID NO 26) [2fG](SEQ ID NO: 119) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] OSC17S- [2fG][mA][2fA][mC][2fU][mG][2fA][mC] 11 [2fA][nnG][2fU][mU][2fU][mC][2fU][mU][2fG] 11 [2fA][mA][2fG][mA][2fA][mA][2fC][mU] [mU][2fC][mA][2fG][mU][2fU][mC](SEQ ID [2fG][mC][2fG][mC][2fA][mA][2fC][mU] NO 27) [2fG](SEQ ID NO: 120) OSC17A- [2fC][mA][2fG][mU][2fU][mG][2fC][mG][2fC] OSC17S- [mG][2fA][mA][2fC][mU][2fG][mA][2fC] 12 [mA][2fG][mU][2fU][mU][2fC][mU][2fU][mG] 12 [mA][2fA][mG][2fA][mA][2fA][mC][2fU] [2fU][mC][2fA][mG][2fU][mU][2fC][dT]*[dT] [mG][2fC][mG][2fC][mA][2fA][mC][2fU] (SEQ ID NO 28) [mG][dT]*[dT](SEQ ID NO: 121) OSC17A- [2fC][mA][2fG][mU][2fU][mG][2fC][mG][2fC] OSC17S- [mG][2fA][mA][2fC][mU][2fG][mA][2fC] 13 [mA][2fG][mU][2fU][mU][2fC][mU][2fU][mG] 13 [mA][2fA][mG][2fA][mA][2fA][mC] [2fU][mC][2fA][mG][2fU][mU][2fC](SEQ ID [2fU][mG][2fC][mG][2fC][mA][2fA][mC] NO 29) [2fU][mG](SEQ ID NO: 122) OSC17A- [mC][2fA][2fG][2fU][2fU][2fG][2fC][2fG] OSC17S- [2fU][mG][2fA][mC][2fA][mA][2fG][mA] 14 [2fC][2fA][2fG][2fU][2fU][2fU][2fC][2fU] 14 [2fA][mA][2fC][mU][2fG][mC][2fG][mC] [2fU][2fG][2fU][2fC][2fA][2fG][2fU][2fU] [2fA][mA][2fC][mU][2fG][dT]*[dT](SEQ  [2fC][dT]*[dT](SEQ ID NO 30) ID NO: 123) OSC17A- [mC][2fA][2fG][2fU][2fU][2fG][2fC][2fG] OSC17S- [2fG][mA][2fA][mA][2fC][mU][2fG][mC] 15 [2fC][2fA][2fG][2fU][2fU][2fU][2fC][2fU] 15 [2fG][mC][2fA][mA][2fC][mU][2fG][dT]* [2fU][2fG][2fU][2fC][2fA][2fG][2fU][2fU] [dT](SEQ ID NO: 124) [2fC][dT]*[dT](SEQ ID NO 31) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] OSC17S- [2fG][mA][2fA][mA][2fC][mU][2fG][mC] 16 [2fA][G][2fU][mU][2fU][mC][2fU][mU][2fG] 16 [2fG][mC][2fA][mA][2fC][mU][2fG][dT]* [mU][2fC][mA][2fG][mU][2fU][mC][dT]*[dT] [dT](SEQ ID NO: 125) (SEQ ID NO 32) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] OSC17S- [2fG][mA][2fA][mA][2fC][mU][2fG][mC] 17 [2fA][mG][2fU][mU][2fU][mC][2fU][mU][2fG] 17 [2fG][mC][2fA][mA][2fC][mU][2fG](SEQ  [mU][2fC][mA][2fG][mU](SEQ ID NO 33) ID NO: 126) OSC17A- [mC][2fA][mG][2fU][mU][2fG][mC][2fG][mC] OSC17S- [2fG][mA][2fA][mA][2fC][mU][2fG][mC] 18 [2fA][mG][2fU][mU][2fU][mC][2fU][2fU] 18 [2fG][mC][2fA][mA][2fC][mU][2fG](SEQ  [2fG][2fU][2fC][2fA][2fG][2fU](SEQ ID  ID NO: 127) NO 34) OSC18A AUGCAGUCAUCGCUCAGCGUG[dT][dT](SEQ  OSC18S CACGCUGAGCGAUGACUGCAU[dT][dT] ID NO 35) (SEQ ID NO: 128) OSC19A AAUGCAGUCAUCGCUCAGCGU[dT][dT](SEQ  OSC19S ACGCUGAGCGAUGACUGCAUU[dT][dT] ID NO 36) (SEQ ID NO: 129) OSC20A UGGAAUGCAGUCAUCGCUCAG[dT][dT](SEQ  OSC20S CUGAGCGAUGACUGCAUUCCA[dT][dT] ID NO 37) (SEQ ID NO: 130) OSC21A AGUGGAAUGCAGUCAUCGCUC[dT][dT](SEQ  OSC21S GAGCGAUGACUGCAUUCCACU[dT][dT] ID NO 38) (SEQ ID NO: 131) OSC22A ACAGUCUGGGUGGCCGUCGCA[dT][dT](SEQ  OSC22S UGCGACGGCCACCCAGACUGU[dT][dT] ID NO 39) (SEQ ID NO: 132) OSC23A AUUGGUUCCACAGCCGAGCUC[dT][dT](SEQ  OSC23S GAGCUCGGCUGUGGAACCAAU[dT][dT] ID NO 40) (SEQ ID NO: 133) OSC24A UCUCAUUGGUUCCACAGCCGA[dT][dT](SEQ  OSC24S UCGGCUGUGGAACCAAUGAGA[dT][dT] ID NO 41) (SEQ ID NO: 134) OSC25A AUCUCAUUGGUUCCACAGCCG[dT][dT](SEQ  OSC25S CGGCUGUGGAACCAAUGAGAU[dT][dT] ID NO 42) (SEQ ID NO: 135) OSC26A AGGAUCUCAUUGGUUCCACAG[dT][dT](SEQ  OSC26S CUGUGGAACCAAUGAGAUCCU[dT][dT] ID NO 43) (SEQ ID NO: 136) OSC27A UGAGAGAGGUGACACUCUCCA[dT][dT](SEQ  OSC27S UGGAGAGUGUCACCUCUCUCA[dT][dT] ID NO 44) (SEQ ID NO: 137) OSC28A UGGUUGUGGCAUUCCUGAGAG[dT][dT] OSC28S CUCUCAGGAAUGCCACAACCA[dT][dT] (SEQ ID NO 45) (SEQ ID NO: 138) OSC29A UGGCAUUCCCGACAGAGGGGA[dT][dT](SEQ  OSC29S UCCCCUCUGUCGGGAAUGCCA[dT][dT] ID NO 46) (SEQ ID NO: 139) OSC30A AGGAUGUGGCAUUCCCGACAG[dT][dT](SEQ  OSC30S CUGUCGGGAAUGCCACAUCCU[dT][dT] ID NO 47) (SEQ ID NO: 140) OSC31A UUCCAGACUGGUCUCCGGCAG[dT][dT](SEQ  OSC31S CUGCCGGAGACCAGUCUGGAA[dT][dT] ID NO 48) (SEQ ID NO: 141) OSC32A AUAACCCCAUAGGCAGUUGGG[dT][dT](SEQ  OSC32S CCCAACUGCCUAUGGGGUUAU[dT][dT] ID NO 49) (SEQ ID NO: 142) OSC33A UUGCACUGAGCACCGCAGCAG[dT][dT](SEQ  OSC33S CUGCUGCGGUGCUCAGUGCAA[dT][dT] ID NO 50) (SEQ ID NO: 143) OSC34A AAAAGGAGGAGGGUGGCGGUG[dT][dT](SEQ  OSC34S CACCGCCACCCUCCUCCUUUU[dT][dT] ID NO 51) (SEQ ID NO: 144) OSC35A ACAAAAGGAGGAGGGUGGCGG[dT][dT](SEQ  OSC35S CCGCCACCCUCCUCCUUUUGU[dT][dT] ID NO 52) (SEQ ID NO: 145) OSC36A ACCAGUAACCCCAGUGGGCGG[dT][dT](SEQ  OSC36S CCGCCCACUGGGGUUACUGGU[dT][dT] ID NO 53) (SEQ ID NO: 146) OSC37A UUCAUGGCCACCAGUAACCCC[dT][dT](SEQ  OSC37S GGGGUUACUGGUGGCCAUGAA[dT][dT] ID NO 54) (SEQ ID NO: 147) OSC38A ACUCCUUCAUGGCCACCAGUA[dT][dT](SEQ  OSC38S UACUGGUGGCCAUGAAGGAGU[dT][dT] ID NO 55) (SEQ ID NO: 148) OSC39A UUCUGACAGCAGCAGGGACUC[dT][dT](SEQ  OSC39S GAGUCCCUGCUGCUGUCAGAA[dT][dT] ID NO 56) (SEQ ID NO: 149) OSC40A UCUGUUCUGACAGCAGCAGGG[dT][dT](SEQ  OSC40S GGCUGCUGCUGUCAGAACAGA[dT][dT] ID NO 57) (SEQ ID NO: 150) OSC41A UCUUCUGUUCUGACAGCAGCA[dT][dT](SEQ  OSC41S UGCUGCUGUCAGAACAGAAGA[dT][dT] ID NO 58) (SEQ ID NO: 151) OSC42A AGGUCUUCUGUUCUGACAGCA[dT][dT](SEQ  OSC42S UGCUGUCAGAACAGAAGACCU[dT][dT] ID NO 59) (SEQ ID NO: 152) OSC43A UUGUCCUCAGGGCAGCGAGGU[dT][dT](SEQ  OSC43S ACCUCGCUGCCCUGAGGACAA[dT][dT] ID NO 60) (SEQ ID NO: 153) OSC44A AAGUGCUUGUCCUCAGGGCAG[dT][dT](SEQ  OSC44S CUGCCCUGAGGACAAGCACUU[dT][dT] ID NO 61) (SEQ ID NO: 154) OSC45A UACCCAUCCGCAUCACUGCUC[dT][dT](SEQ  OSC45S GAGCAGUGAUGCGGAUGGGUA[dT][dT] ID NO 62) (SEQ ID NO: 155) OSC46A UCUCUGAGGGCUGGUGUGCCC[dT][dT](SEQ  OSC46S GGGCACACCAGCCCUCAGAGA[dT][dT] ID NO 63) (SEQ ID NO: 156) OSC47A- AAGAGCUCAGGUCUCUGAGGG[dT][dT](SEQ  OSC475- CCCUCAGAGACCUGAGCUCUU[dT][dT] 1 ID NO 64) 1 (SEQ ID NO: 157) OSC47A- AAGAGCUCAGGUCUCUGAGGG[dT]*[dT] OSC47S- CCCUCAGAGACCUGAGCUCUU[dT]*[dT] 2 (SEQ ID NO 65) 2 (SEQ ID NO: 158) OSC47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] OSC47S- [mC][mC][mC][mU][mC][mA][mG][mA] 3 [mG][mG][mU][mC][mU][mC][mU][mG][mA] 3 [mG][mA][mC][mC][mU][mG][mA][mG] [mG][mG][mG][dT]*[dT](SEQ ID NO 66) [mC][mU][mC][mU][mU][dT]*[dT](SEQ ID NO: 159) OSC47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] OSC47S- [mC][mC][mC][mU][mC][mA][mG][mA] 4 [mG][mG][mU][mC][mU][mC][mU][mG][mA] 4 [mG][mA][mC][mC][mU][mG][mA][mG] [mG][mG][mG][dT]*[dT](SEQ ID NO 67) [mC][mU][mC][mU][mU](SEQ ID NO: 160) OSC47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] OSC47S- [mC][mC][mC][mU][mC][mA][mG][mA] 5 [mG][mG][mU][mC][mU][mC][mU][mG][mA] 5 [mG][mA][mC][mC][mU][mG][mA][mG] [mG][mG][mG](SEQ ID NO 68) [mC][mU][mC][mU][mU][dT]*[dT](SEQ ID NO: 161) OSC47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] OSC47S- [mC][mC][mC][mU][mC][mA][mG][mA] 6 [mG][mG][mU][mC][mU][mC][mU][mG][mA] 6 [mG][mA][mC][mC][mU][mG][mA][mG] [mG][mG][mG](SEQ ID NO 69) [mC][mU][mC][mU][mU](SEQ ID NO: 162) OSC47A- [mA][mA][mG][mA][mG][mC][mU][mC][mA] OSC47S- CCCUCAGAGACCUGAGCUCUU[dT]*[dT] 7 [mG][mG][mU][mC][mU][mC][mU][mG][mA] 7 (SEQ ID NO: 163) [mG][mG][mG][dT]*[dT](SEQ ID NO 70) OSC47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC][mA] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG][mA] 8 [2fG][mG][2fU][mC][2fU][mC][2fU][mG][2fA] 8 [2fG][mA][2fC][mC][2fU][mG][2fA][mG] [mG][2fG][mG][dT]*[dT](SEQ ID NO 71) [2fC][mU][2fC][mU][2fU][dT]*[dT](SEQ ID NO: 164) OSC47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC][mA] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG][mA] 9 [2fG][mG][2fU][mC][2fU][mC][2fU][mG][2fA] 9 [2fG][mA][2fC][mC][2fU][mG][2fA][mG] [mG][2fG][mG](SEQ ID NO 72) [2fC][mU][2fC][mU][2fU][dT]*[dT](SEQ ID NO: 165) OSC47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC][mA] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG][mA] 10 [2fG][mG][2fU][mC][2fU][mC][2fU][mG][2fA] 10 [2fG][mA][2fC][mC][2fU][mG][2fA][mG] [mG][2fG][mG][dT]*[dT](SEQ ID NO 73) [2fC][mU][2fC][mU][2fU](SEQ ID NO: 166) SC47A- [mA][2fA][mG][2fA][mG][2fC][mU][2fC][mA] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG]][mA] 11 [2fG][mG][2fU][mC][2fU][mC][2fU][mG][2fA] 11 [2fG[mA][2fC][mC][2fU][mG][2fA][mG] [mG][2fG][mG](SEQ ID NO 74) [2fC][mU][2fC][mU][2fU](SEQ ID NO: 167) OSC47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC][2fA] OSC47S- [mC][2fC][mC][2fU][mC][2fA][mG][2fA] 12 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] 12 [mG][2fA][mC][2fC][mU][2fG][mA][2fG] [2fG][mG][2fG][dT]*[dT](SEQ ID NO 75) [mC][2fU][mC][2fU][mU][dT][dT]*(SEQ ID NO: 168) OSC47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC][2fA] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG][mA] 13 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] 13 [2fG][mA][2fC][mC][2fU][mG][2fA][mG] [2fG][mG][2fG](SEQ ID NO 76) [2fC][mU][2fC][mU][2fU]-LIG-LINKER(SEQ  ID NO: 169) OSC47A- [mA][2fA][2fG][mA][2fG][mC][2fU][mC][2fA] OSC47S- [2fC][mC][2fC][mU][2fC][mA][2fG][mA] 14 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] 14 [2fG][mA][2fC][mC][2fU][mG][2fA][mG] [2fG][mG][2fG](SEQ ID NO 77) [2fC][mU][2fC][mU][2fU][dT]*[dT](SEQ  ID NO: 170) OSC47A- [mA][2fA][2fG][mA][2fG][mC][2fU][mC][2fA] OSC47S- [2fG][mA][2fG][mA][2fC][mC][2fU][mG] 15 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] 15 [2fA][mG][2fC][mU][2fC][mU][2fU][dT]* [2fG][mG][2fG][dT]*[dT](SEQ ID NO 78) [dT](SEQ ID NO: 171) OSC47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC][2fA] OSC47S- [2fG][mA][2fG][mA][2fC][mC][2fU][mG] 16 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] 16 [2fA][mG][2fC][mU][2fC][mU][2fU][dT]* [2fG][mG][2fG][dT]*[dT](SEQ ID NO 79) [dT](SEQ ID NO: 172) OSC47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC][2fA] OSC47S- [2fG][mA][2fG][mA][2fC][mC][2fU][mG] 17 [mG][2fG][mU][2fC][mU][2fC][mU][2fG][mA] 17 [2fA][mG][2fC][mU][2fC][mU][2fU](SEQ  [2fG][mG][2fG][dT]*[dT](SEQ ID NO 80) ID NO: 173) OSC47A- [2fA][mA][2fG][mA][2fG][mC][2fU][mC][2fA] OSC47S- [2fG][mA][2fG][mA][2fC][mC][2fU][mG] 18 [mG][2fG][mU][2fC][mU][2fC][2fU][2fG][2fA] 18 [2fA][mG][2fC][mU][2fC][mU][2fU](SEQ  [2fG][2fG][2fG](SEQ ID NO 81) ID NO: 174) OSC48A AAGAGCUCAGGUCUCUGAGGG[dT][dT](SEQ  OSC48S CCCUCAGAGACCUGAGCUCUU[dT][dT] ID NO 82) (SEQ ID NO: 175) OSC49A AGAAGAGCUCAGGUCUCUGAG[dT][dT](SEQ  OSC49S CUCAGAGACCUGAGCUCUUCU[dT][dT] ID NO: 83) (SEQ ID NO: 176) OSC50A AUAGGGAGUGUCCAGGGACCC[dT][dT](SEQ  OSC50S GGGUCCCUGGACACUCCCUAU[dT][dT] ID NO: 84) (SEQ ID NO: 177) OSC51A UCCAUAGGGAGUGUCCAGGGA[dT][dT](SEQ OSC51S UCCCUGGACACUCCCUAUGGA[dT][dT] ID NO: 85) (SEQ ID NO: 178) OSC52A AUCUCCAUAGGGAGUGUCCAG[dT][dT](SEQ  OSC52S CUGGACACUCCCUAUGGAGAU[dT][dT] ID NO: 86) (SEQ ID NO: 179) OSC53A UCAGUUCUGGCUGUGGCAGGU[dT][dT](SEQ  OSC53S ACCUGCCACAGCCAGAACUGA[dT][dT] ID NO: 87) (SEQ ID NO: 180) OSC54A UUCUACCCCCUGGGAGCUGCC[dT][dT](SEQ  OSC54S GGCAGCUCCCAGGGGGUAGAA[dT][dT] ID NO: 88) (SEQ ID NO: 181) OSC55A AAGCACAGGGCCGUUCUACCC[dT][dT](SEQ  OSC55S GGGUAGAACGGCCCUGUGCUU[dT][dT] ID NO: 89) (SEQ ID NO: 182) OSC56A UGUCUUAAGCACAGGGCCGUU[dT][dT](SEQ  OSC56S AACGGCCCUGUGCUUAAGACA[dT][dT] ID NO: 90) (SEQ ID NO: 183) OSC57A AGUGUCUUAAGCACAGGGCCG[dT][dT](SEQ  OSC57S CGGCCCUGUGCUUAAGACACU[dT][dT] ID NO: 91) (SEQ ID NO: 184) OSC58A UUUUUUGAGGAUGUGAAGCAA[dT][dT] OSC58S UUGCUUCACAUCCUCAAAAAA[dT][dT] (SEQ ID NO: 92) (SEQ ID NO: 185) OSC59A UUUUUUUGAGGAUGUGAAGCA[dT][dT] OSC59S UGCUUCACAUCCUCAAAAAAA[dT][dT] (SEQ ID NO: 93) (SEQ ID NO: 186) 

TABLE 6 LRP2 OS ID Antisense Strand (5' TO 3') OS ID Sense Strand (5' TO 3') OSL1A UACUUUGUGAGCAAUCUUGAC[dT][dT](SEQ  OSL1S  GUCAAGAUUGCUCACAAAGUA[dT][dT] ID NO: 187) (SEQ ID NO: 561) OSL2A AUUCACUUGGGAUACACUGAC[dT][dT](SEQ  OSL2S  GUCAGUGUAUCCCAAGUGAAU[dT][dT] ID NO: 188) (SEQ ID NO: 562) OSL3A ACAUGAAAACUCAUUGUGCAA[dT][dT](SEQ  OSL3S  UUGCACAAUGAGUUUUCAUGU[dT][dT] ID NO: 189) (SEQ ID NO: 563) OSL4A UCUUUACAGUCAUCUUCUCCA[dT][dT](SEQ  OSL4S  UGGAGAAGAUGACUGUAAAGAUA[dT][dT] ID NO: 190) (SEQ ID NO: 564) OSL5A UAUCUUUACAGUCAUCUUCUC[dT][dT](SEQ  OSL5S  GAGAAGAUGACUGUAAAGAUA[dT][dT] ID NO: 191) (SEQ ID NO: 565) OSL6A AACAUUUAUGAACAUCAUGAG[dT][dT](SEQ  OSL6S  CUCAUGAUGUUCAUAAAUGUU[dT][dT] ID NO: 192) (SEQ ID NO: 566) OSL7A UCACAAACUUUAUAAAUGGAG[dT][dT](SEQ  OSL7S  CUCCAUUUAUAAAGUUUGUGA[dT][dT] ID NO: 193) (SEQ ID NO: 567) OSL8A AUCACAAACUUUAUAAAUGGA[dT][dT](SEQ  OSL8S  UCCAUUUAUAAAGUUUGUGAU[dT][dT] ID NO: 194) (SEQ ID NO: 568) OSL9A AUACUACAGUAUUUUCCGGUA[dT][dT](SEQ  OSL9S  UACCGGAAAAUACUGUAGUAU[dT][dT] ID NO: 195) (SEQ ID NO: 569) OSL10A UCAUACUACAGUAUUUUCCGG[dT][dT](SEQ  OSL10S  CCGGAAAAUACUGUAGUAUGA[dT][dT] ID NO: 196) (SEQ ID NO: 570) OSL11A ACAAAUUCCCCAUAUCUGGCA[dT][dT](SEQ  OSL11S  UGCCAGAUAUGGGGAAUUUGU[dT][dT] ID NO: 197) (SEQ ID NO: 571) OSL12A AAGAUAUACCCUUCUUCACAG[dT][dT](SEQ  OSL12S  CUGUGAAGAAGGGUAUAUCUU[dT][dT] ID NO: 198) (SEQ ID NO: 572) OSL13A UUAGCUUUGCAAUACUGUCCA[dT][dT](SEQ  OSL13S UGGACAGUAUUGCAAAGCUAA[dT][dT] ID NO: 199) (SEQ ID NO: 573) OSL14A AUCAUUAGCUUUGCAAUACUG[dT][dT](SEQ  OSL14S  CAGUAUUGCAAAGCUAAUGAU[dT][dT] ID NO: 200) (SEQ ID NO: 574) OSL15A AAAGGAAUCAUUAGCUUUGCA[dT][dT](SEQ  OSL15S  UGCAAAGCUAAUGAUUCCUUU[dT][dT] ID NO: 201) (SEQ ID NO: 575) OSL16A AUGAAUAUCACCAAUUAACAA[dT][dT](SEQ  OSL16S  UUGUUAAUUGGUGAUAUUCAU[dT][dT] ID NO: 202) (SEQ ID NO: 576) OSL17A AAAAAACCUUAUUUUGCACGG[dT][dT](SEQ  OSL17S  CCGUGCAAAAUAAGGUUUUUU[dT][dT] ID NO: 203) (SEQ ID NO: 577) OSL18A UGAAAAAACCUUAUUUUGCAC[dT][dT](SEQ  OSL18S  GUGCAAAAUAAGGUUUUUUCA[dT][dT] ID NO: 204) (SEQ ID NO: 578) OSL19A AAUGUCAACUGAAAAAACCUU[dT][dT](SEQ  OSL19S  AAGGUUUUUUCAGUUGACAUU[dT][dT] ID NO: 205) (SEQ ID NO: 579) OSL20A UAAUGUCAACUGAAAAAACCU[dT][dT](SEQ  OSL20S  AGGUUUUUUCAGUUGACAUUA[dT][dT] ID NO: 206) (SEQ ID NO: 580) OSL21A UUAAACCAUUAAUGUCAACUG[dT][dT](SEQ  OSL21S  CAGUUGACAUUAAUGGUUUAA[dT][dT] ID NO: 207) (SEQ ID NO: 581) OSL22A UAUUUAAACCAUUAAUGUCAA[dT][dT](SEQ  OSL22S  UUGACAUUAAUGGUUUAAAUA[dT][dT] ID NO: 208) (SEQ ID NO: 582) OSL23A UAGAUUUUAUUAUUAACCCAG[dT][dT](SEQ  OSL23S CUGGGUUAAUAAUAAAAUCUA[dT][dT] ID NO: 209) (SEQ ID NO: 583) OSL24A AUAGAUUUUAUUAUUAACCCA[dT][dT](SEQ  OSL24S  UGGGUUAAUAAUAAAAUCUAU[dT][dT] ID NO: 210) (SEQ ID NO: 584) OSL25A AAAUUUACCAUAUCUAUGCGG[dT][dT](SEQ  OSL25S  CCGCAUAGAUAUGGUAAAUUU[dT][dT] ID NO: 211) (SEQ ID NO: 585) OSL26A AAGUUUUCAGUUAUAAGGGUA[dT][dT](SEQ  OSL26S  UACCCUUAUAACUGAAAACUU[dT][dT] ID NO: 212) (SEQ ID NO: 586) OSL27A AAUAAAUAACCAACAGUUGGG[dT][dT](SEQ  OSL27S  CCCAACUGUUGGUUAUUUAUU[dT][dT] ID NO: 213) (SEQ ID NO: 587) OSL28A AGAAAAAUAAAUAACCAACAG[dT][dT](SEQ  OSL28S  CUGUUGGUUAUUUAUUUUUCU[dT][dT] ID NO: 214) (SEQ ID NO: 588) OSL29A AUAUCAUAUCCAGAGUUACCC[dT][dT](SEQ  OSL29S  GGGUAACUCUGGAUAUGAUAU[dT][dT] ID NO: 215) (SEQ ID NO: 589) OSL30A AGUUUCAAUGUAAUCAAACCG[dT][dT](SEQ  OSL30S  CGGUUUGAUUACAUUGAAACU[dT][dT] ID NO: 216) (SEQ ID NO: 590) OSL31A UUACAGUUUCAAUGUAAUCAA[dT][dT](SEQ  OSL31S UUGAUUACAUUGAAACUGUAA[dT][dT] ID NO: 217) (SEQ ID NO: 591) OSL32A AUAAGUUACAGUUUCAAUGUA[dT][dT](SEQ  OSL32S  UACAUUGAAACUGUAACUUAU[dT][dT] ID NO: 218) (SEQ ID NO: 592) OSL33A UCUUUACACGGAUUGGUAGCA[dT][dT](SEQ  OSL33S  UGCUACCAAUCCGUGUAAAGA[dT][dT] ID NO: 219) (SEQ ID NO: 593) OSL34A AAAAUCAAUCCCGACAAAGAA[dT][dT](SEQ  OSL34S  UUCUUUGUCGGGAUUGAUUUU[dT][dT] ID NO: 220) (SEQ ID NO: 594) OSL35A UCUGAAAAAAAGAUAGUGCUG[dT][dT](SEQ  OSL35S  CAGCACUAUCUUUUUUUCAGA[dT][dT] ID NO: 221) (SEQ ID NO: 595) OSL36A AUCUGAAAAAAAGAUAGUGCU[dT][dT](SEQ  OSL36S  AGCACUAUCUUUUUUUCAGAU[dT][dT] ID NO: 222) (SEQ ID NO: 596) OSL37A AAAAAUCAUGUGUUUUGACAU[dT][dT](SEQ  OSL37S AUGUCAAAACACAUGAUUUUU[dT][dT] ID NO: 223) (SEQ ID NO: 597) OSL38A UUUGCUUAAAAAUCAUGUGUU[dT][dT](SEQ  OSL38S  AACACAUGAUUUUUAAGCAAA[dT][dT] ID NO: 224) (SEQ ID NO: 598) OSL39A AACUUUCAACAUUUUCCACCC[dT][dT](SEQ  OSL39S  GGGUGGAAAAUGUUGAAAGUU[dT][dT] ID NO: 225) (SEQ ID NO: 599) OSL40A UUGAAAUCCAAUCAAAAGCCA[dT][dT](SEQ  OSL40S  UGGCUUUUGAUUGGAUUUCAA[dT][dT] ID NO: 226) (SEQ ID NO: 600) OSL41A UUUGAAAUCCAAUCAAAAGCC[dT][dT](SEQ  OSL41S  GGCUUUUGAUUGGAUUUCAAA[dT][dT] ID NO: 227) (SEQ ID NO: 601) OSL42A UAGAGAUUCUUUGAAAUCCAA[dT][dT](SEQ  OSL42S  UUGGAUUUCAAAGAAUCUCUA[dT][dT] ID NO: 228) (SEQ ID NO: 602) OSL43A AUAGAGAUUCUUUGAAAUCCA[dT][dT](SEQ  OSL43S  UGGAUUUCAAAGAAUCUCUAU[dT][dT] ID NO: 229) (SEQ ID NO: 603) OSL44A UUUAAAUACUGAACUACUGUG[dT][dT](SEQ  OSL44S  CACAGUAGUUCAGUAUUUAAA[dT][dT] ID NO: 230) (SEQ ID NO: 604) OSL45A UAUUUAAAUACUGAACUACUG[dT][dT](SEQ  OSL45S  CAGUAGUUCAGUAUUUAAAUA[dT][dT] ID NO: 231) (SEQ ID NO: 605) OSL46A AUAGAUACCCGGCAAAAGGAU[dT][dT](SEQ  OSL46S  AUCCUUUUGCCGGGUAUCUAU[dT][dT] ID NO: 232) (SEQ ID NO: 606) OSL47A AAGAGUAGUGUUUAUUACAGG[dT][dT](SEQ  OSL47S  CCCCUGUAAUAAACACUACUC[dT][dT] ID NO: 233) (SEQ ID NO: 607) OSL48A AUCAAAAUAGGCAUCUACCCA[dT][dT](SEQ  OSL48S  UGGGUAGAUGCCUAUUUUGAU[dT][dT] ID NO: 234) (SEQ ID NO: 608) OSL49A UCAAUUUUAUCAAAAUAGGCA[dT][dT](SEQ  OSL49S  UGCCUAUUUUGAUAAAAUUGA[dT][dT] ID NO: 235) (SEQ ID NO: 609) OSL50A UAAAUGCUCUCCAAAGAUGGC[dT][dT](SEQ  OSL50S  GCCAUCUUUGGAGAGCAUUUA[dT][dT] ID NO: 236) (SEQ ID NO: 610) OSL51A UCAAAUGCAGUAUGUAAGCAA[dT][dT](SEQ  OSL51S  UUGCUUACAUACUGCAUUUGA[dT][dT] ID NO: 237) (SEQ ID NO: 611) OSL52A UUCAAAUGCAGUAUGUAAGCA[dT][dT](SEQ  OSL52S  UGCUUACAUACUGCAUUUGAA[dT][dT] ID NO: 238) (SEQ ID NO: 612) OSL53A UGAUUACAGGCGUUAGAACCA[dT][dT](SEQ  OSL53S  UGGUUCUAACGCCUGUAAUCA[dT][dT] ID NO: 239) (SEQ ID NO: 613) OSL54A UGUUAUCAUGACAAUCAUCGA[dT][dT](SEQ  OSL545  UCGAUGAUUGUCAUGAUAACA[dT][dT] ID NO: 240) (SEQ ID NO: 614) OSL55A UUAUCACAGGUGUAUUGGGUG[dT][dT](SEQ  OSL55S CACCCAAUACACCUGUGAUAA[dT][dT] ID NO: 241) (SEQ ID NO: 615) OSL56A AUUAUCACAGGUGUAUUGGGU[dT][dT](SEQ  OSL56S  ACCCAAUACACCUGUGAUAAU[dT][dT] ID NO: 242) (SEQ ID NO: 616) OSL57A AGUUCUUUGAGAUACACUGGU[dT][dT](SEQ  OSL57S  ACCAGUGUAUCUCAAAGAACU[dT][dT] ID NO: 243) (SEQ ID NO: 617) OSL58A UCGAAUUGCAGUUCUUUUCAU[dT][dT](SEQ  OSL58S  AUGAAAAGAACUGCAAUUCGA[dT][dT] ID NO: 244) (SEQ ID NO: 618) OSL59A UCAAUACAUCGAUGAUUGGGG[dT][dT](SEQ  OSL59S  CCCCAAUCAUCGAUGUAUUGA[dT][dT] ID NO: 245) (SEQ ID NO: 619) OSL60A AACGAUAGGUCAAUACAUCGA[dT][dT](SEQ  OSL60S  UCGAUGUAUUGACCUAUCGUU[dT][dT] ID NO: 246) (SEQ ID NO: 620) OSL61A ACAAACGAUAGGUCAAUACAU[dT][dT](SEQ  OSL61S  AUGUAUUGACCUAUCGUUUGU[dT][dT] ID NO: 247) (SEQ ID NO: 621) OSL62A UCAAAAACACCAUCACAACGA[dT][dT](SEQ  OSL62S  UCGUUGUGAUGGUGUUUUUGA[dT][dT] ID NO: 248) (SEQ ID NO: 622) OSL63A UCACAUUCCCAGAAGUUCGGG[dT][dT](SEQ  OSL63S  CCCGAACUUCUGGGAAUGUGA[dT][dT] ID NO: 249) (SEQ ID NO: 623) OSL64A AUCACAUUCCCAGAAGUUCGG[dT][dT](SEQ  OSL64S  CCGAACUUCUGGGAAUGUGAU[dT][dT] ID NO: 250) (SEQ ID NO: 624) OSL65A UGAUGAAGGGCAAGUCUUGGG[dT][dT](SEQ  OSL65S  CCCAAGACUUGCCCUUCAUCA[dT][dT] ID NO: 251) (SEQ ID NO: 625) OSL66A AGAAUCAUUGGCAAGUAAGAA[dT][dT](SEQ  OSL66S  UUCUUACUUGCCAAUGAUUCU[dT][dT] ID NO: 252) (SEQ ID NO: 626) OSL67A UAUCACAUUCAUCUAUGUCUU[dT][dT](SEQ  OSL67S  AAGACAUAGAUGAAUGUGAUA[dT][dT] ID NO: 253) (SEQ ID NO: 627) OSL68A AAUAUCACAUUCAUCUAUGUC[dT][dT](SEQ  OSL68S  GACAUAGAUGAAUGUGAUAUU[dT][dT] ID NO: 254) (SEQ ID NO: 628) OSL69A AACAUGUAGCCUGUAUCACAC[dT][dT](SEQ  OSL69S  GUGUGAUACAGGCUACAUGUU[dT][dT] ID NO: 255) (SEQ ID NO: 629) OSL70A UCACUUUCUAACAUGUAGCCU[dT][dT](SEQ  OSL70S  AGGCUACAUGUUAGAAAGUGA[dT][dT] ID NO: 256) (SEQ ID NO: 630) OSL71A AUCACUUUCUAACAUGUAGCC[dT][dT](SEQ  OSL71S  GGCUACAUGUUAGAAAGUGAU[dT][dT] ID NO: 257) (SEQ ID NO: 631) OSL72A AAUGUAAGAACCAUUCUCGAC[dT][dT](SEQ  OSL72S  GUCGAGAAUGGUUCUUACAUU[dT][dT] ID NO: 258) (SEQ ID NO: 632) OSL73A UACAAUGUAAGAACCAUUCUC[dT][dT](SEQ  OSL73S  GAGAAUGGUUCUUACAUUGUA[dT][dT] ID NO: 259) (SEQ ID NO: 633) OSL74A AAAAUCAACAGCUACAAUGUA[dT][dT](SEQ  OSL74S  UACAUUGUAGCUGUUGAUUUU[dT][dT] ID NO: 260) (SEQ ID NO: 634) OSL75A AUUGAAUCAAAAUCAACAGCU[dT][dT](SEQ  OSL75S  AGCUGUUGAUUUUGAUUCAAU[dT][dT] ID NO: 261) (SEQ ID NO: 635) OSL76A UAAUUGAAUCAAAAUCAACAG[dT][dT](SEQ  OSL76S  CUGUUGAUUUUGAUUCAAUUA[dT][dT] ID NO: 262) (SEQ ID NO: 636) OSL77A AAGAUACGACCACUAAUUGAA[dT][dT](SEQ  OSL77S  UUCAAUUAGUGGUCGUAUCUU[dT][dT] ID NO: 263) (SEQ ID NO: 637) OSL78A AGUUUCAGUCAAGAUGAUGCU[dT][dT](SEQ  OSL78S  AGCAUCAUCUUGACUGAAACU[dT][dT] ID NO: 264) (SEQ ID NO: 638) OSL79A AAUAGUUUCAGUCAAGAUGAU[dT][dT](SEQ  OSL795  AUCAUCUUGACUGAAACUAUU[dT][dT] ID NO: 265) (SEQ ID NO: 639) OSL80A UAUUGCAAUAGUUUCAGUCAA[dT][dT](SEQ  OSL80S UUGACUGAAACUAUUGCAAUA[dT][dT] ID NO: 266) (SEQ ID NO: 640) OSL81A UCUAUUGCAAUAGUUUCAGUC[dT][dT](SEQ  OSL81S GACUGAAACUAUUGCAAUAGA[dT][dT] ID NO: 267) (SEQ ID NO: 641) OSL82A AAUCUAUUGCAAUAGUUUCAG[dT][dT](SEQ  OSL82S  CUGAAACUAUUGCAAUAGAUU[dT][dT] ID NO: 268) (SEQ ID NO: 642) OSL83A AUUUUGGAGACUUCAAUUGUU[dT][dT](SEQ  OSL83S  AACAAUUGAAGUCUCCAAAAU[dT][dT] ID NO: 269) (SEQ ID NO: 643) OSL84A UUAGGUUUUUACUAAUCAGCA[dT][dT](SEQ  OSL84S  UGCUGAUUAGUAAAAACCUAA[dT][dT] ID NO: 270) (SEQ ID NO: 644) OSL85A UCAUUCUGGGAUCUAAUGCUA[dT][dT](SEQ  OSL85S UAGCAUUAGAUCCCAGAAUGA[dT][dT] ID NO: 271) (SEQ ID NO: 645) OSL86A UUCAUUCUGGGAUCUAAUGCU[dT][dT](SEQ  OSL86S  AGCAUUAGAUCCCAGAAUGAA[dT][dT] ID NO: 272) (SEQ ID NO: 646) OSL87A AGUAGAUGCUCAUUCAUUCUG[dT][dT](SEQ  OSL87S CAGAAUGAAUGAGCAUCUACU[dT][dT] ID NO: 273) (SEQ ID NO: 647) OSL88A AUUAUAAUCACAAAAGUCCAU[dT][dT](SEQ  OSL88S  AUGGACUUUUGUGAUUAUAAU[dT][dT] ID NO: 274) (SEQ ID NO: 648) OSL89A UCCAUUAUAAUCACAAAAGUC[dT][dT](SEQ  OSL89S  GACUUUUGUGAUUAUAAUGGA[dT][dT] ID NO: 275) (SEQ ID NO: 649) OSL90A UGCCGUAUAAUCAAAUCAC[dT][dT](SEQ  OSL90S  GUGUGAUUUGAUUAUACGGCA[dT][dT] ID NO: 276) (SEQ ID NO: 650) OSL91A AUAUUAUACAUUACAACUGAC[dT][dT](SEQ  OSL91S GUCAGUUGUAAUGUAUAAUAU[dT][dT] ID NO: 277) (SEQ ID NO: 651) OSL92A AUUGAAUAUUAUACAUUACAA[dT][dT](SEQ  OSL92S  UUGUAAUGUAUAAUAUUCAAU[dT][dT] ID NO: 278) (SEQ ID NO: 652) OSL93A AAUUUGGUUGUUUCGAAGGAU[dT][dT](SEQ  OSL93S  AUCCUUCGAAACAACCAAAUU[dT][dT] ID NO: 279) (SEQ ID NO: 653) OSL94A ACGGAAUUUGGUUGUUUCGAA[dT][dT](SEQ  OSL94S  UUCGAAACAACCAAAUUCCGU[dT][dT] ID NO: 280) (SEQ ID NO: 654) OSL95A UUACAGUUAUUAAGAAAGGUU[dT][dT](SEQ  OSL95S  AACCUUUCUUAAUAACUGUAA[dT][dT] ID NO: 281) (SEQ ID NO: 655) OSL96A UCCAAAAAUUAUAUGUUGCCU[dT][dT](SEQ  OSL96S  AGGCAACAUAUAAUUUUUGGA[dT][dT] ID NO: 282) (SEQ ID NO: 656) OSL97A UUCCAAAAAUUAUAUGUUGCC[dT][dT](SEQ  OSL97S  GGCAACAUAUAAUUUUUGGAA[dT][dT] ID NO: 283) (SEQ ID NO: 657) OSL98A UCUAAACCAUUCUGUAUCCCU[dT][dT](SEQ  OSL98S  AGGGAUACAGAAUGGUUUAGA[dT][dT] ID NO: 284) (SEQ ID NO: 658) OSL99A AUCUAAACCAUUCUGUAUCCC[dT][dT](SEQ  OSL99S  GGGAUACAGAAUGGUUUAGAU[dT][dT] ID NO: 285) (SEQ ID NO: 659) OSL100A UUCAACAUCUAAACCAUUCUG[dT][dT](SEQ  OSL100S CAGAAUGGUUUAGAUGUUGAA[dT][dT] ID NO: 286) (SEQ ID NO: 660) OSL101A AUUUUCAACCCAAUAGAUGUA[dT][dT](SEQ  OSL101S UACAUCUAUUGGGUUGAAAAU[dT][dT] ID NO: 287) (SEQ ID NO: 661) OSL102A UAUAGAAGCAAAUACUGUCCU[dT][dT](SEQ  OSL102S AGGACAGUAUUUGCUUCUAUA[dT][dT] ID NO: 288) (SEQ ID NO: 662) OSL103A UAGAUAUAGAAGCAAAUACUG[dT][dT](SEQ  OSL103S CAGUAUUUGCUUCUAUAUCUA[dT][dT] ID NO: 289) (SEQ ID NO: 663) OSL104A UAAGGCCAGGUUCAUAGAAGG[dT][dT](SEQ  OSL104S CCUUCUAUGAACCUGGCCU[dT][dT](SEQ  ID NO: 290) ID NO: 664) OSL105A UCUUGAAAUCCAAUCUAAGGC[dT][dT](SEQ  OSL105S GCCUUAGAUUGGAUUUCAAGA[dT][dT] ID NO: 291) (SEQ ID NO: 665) OSL106A AUAAAGGUUUCUUGAAAUCCA[dT][dT](SEQ  OSL106S UGGAUUUCAAGAAACCUUUAU[dT][dT] ID NO: 292) (SEQ ID NO: 666) OSL107A UCAAAACCUCGAUUGACUGAG[dT][dT](SEQ  OSL107S CUCAGUCAAUCGAGGUUUUGA[dT][dT] ID NO: 293) (SEQ ID NO: 667) OSL108A UUCUGUAUCUGAUAUCUCCGU[dT][dT](SEQ  OSL108S ACGGAGAUAUCAGAUACAGAA[dT][dT] ID NO: 294) (SEQ ID NO: 668) OSL109A UUUCUGUAUCUGAUAUCUCCG[dT][dT](SEQ  OSL109S CGGAGAUAUCAGAUACAGAAA[dT][dT] ID NO: 295) (SEQ ID NO: 669) OSL110A UUUUUCUGUAUCUGAUAUCUC[dT][dT](SEQ  OSL110S GAGAUAUCAGAUACAGAAAAA[dT][dT] ID NO: 296) (SEQ ID NO: 670) OSL111A AUCAAUGUUUUUCUGUAUCUG[dT][dT](SEQ  OSL111S CAGAUACAGAAAAACAUUGAU[dT][dT] ID NO: 297) (SEQ ID NO: 671) OSL112A AUAAAGGAAAGAAUCAUGGAC[dT][dT](SEQ  OSL112S GUCCAUGAUUCUUUCCUUUAU[dT][dT] ID NO: 298) (SEQ ID NO: 672) OSL113A AAUAAAGGAAAGAAUCAUGGA[dT][dT](SEQ  OSL113S UCCAUGAUUCUUUCCUUUAUU[dT][dT] ID NO: 299) (SEQ ID NO: 673) OSL114A UCAGUAUAAUAAAGGAAAGAA[dT][dT](SEQ  OSL114S UUCUUUCCUUUAUUAUACUGA[dT][dT] ID NO: 300) (SEQ ID NO: 674) OSL115A UUUCAAUGACCUCAUACUGUU[dT][dT](SEQ  OSL115S AACAGUAUGAGGUCAUUGAAA[dT][dT] ID NO: 301) (SEQ ID NO: 675) OSL116A AUUUGGAACAUUAUCUCUCAA[dT][dT](SEQ  OSL116S UUGAGAGAUAAUGUUCCAAAU[dT][dT] ID NO: 302) (SEQ ID NO: 676) OSL117A AGAUUUGGAACAUUAUCUCUC[dT][dT](SEQ  OSL117S GAGAGAUAAUGUUCCAAAUCU[dT][dT] ID NO: 303) (SEQ ID NO: 677) OSL118A UCAGAUUUGGAACAUUAUCUC[dT][dT](SEQ  OSL118S GAGAUAAUGUUCCAAAUCUGA[dT][dT] ID NO: 304) (SEQ ID NO: 678) OSL119A UUGCUACAGCCAUUUGAGG[dT][dT](SEQ ID  OSL119S CCUCAAAUGGCUGUAGCAA[dT][dT](SEQ  NO: 305) ID NO: 679) OSL120A AUGAAAGAGUUAUAUGGAGAG[dT][dT](SEQ  OSL120S CUCUCCAUAUAACUCUUUCAU[dT][dT] ID NO: 306) (SEQ ID NO: 680) OSL121A ACAAUGAAAGAGUUAUAUGGA[dT][dT](SEQ  OSL121S UCCAUAUAACUCUUUCAUUGU[dT][dT] ID NO: 307) (SEQ ID NO: 681) OSL122A UGAAACAACAAUGAAAGAGUU[dT][dT](SEQ  OSL122S AACUCUUUCAUUGUUGUUUCA[dT][dT] ID NO: 308) (SEQ ID NO: 682) OSL123A AUUGAAACAACAAUGAAAGAG[dT][dT](SEQ  OSL123S CUCUUUCAUUGUUGUUUCAAU[dT][dT] ID NO: 309) (SEQ ID NO: 683) OSL124A AGCUAAAGCCUCUGAUUGCAG[dT][dT](SEQ  OSL124S CUGCAAUCAGAGGCUUUAGCU[dT][dT] ID NO: 310) (SEQ ID NO: 684) OSL125A AAGCUAAAGCCUCUGAUUGCA[dT][dT](SEQ  OSL125S UGCAAUCAGAGGCUUUAGCUU[dT][dT] ID NO: 311) (SEQ ID NO: 685) OSL126A ACAAUUCCAAGCUAAAGCCUC[dT][dT](SEQ  OSL126S GAGGCUUUAGCUUGGAAUUGU[dT][dT] ID NO: 312) (SEQ ID NO: 686) OSL127A UGACAAUUCCAAGCUAAAGCC[dT][dT](SEQ  OSL127S GGCUUUAGCUUGGAAUUGUCA[dT][dT] ID NO: 313) (SEQ ID NO: 687) OSL128A UGAAUGAUCUGACAAUUCCAA[dT][dT](SEQ  OSL128S UUGGAAUUGUCAGAUCAUUCA[dT][dT] ID NO: 314) (SEQ ID NO: 688) OSL129A AUGUUCAUCAGAGAAGAUCCA[dT][dT](SEQ  OSL129S UGGAUCUUCUCUGAUGAACAU[dT][dT] ID NO: 315) (SEQ ID NO: 689) OSL130A UAUUCCAUGUGUCACAAUGUU[dT][dT](SEQ  OSL130S AACAUUGUGACACAUGGAAUA[dT][dT] ID NO: 316) (SEQ ID NO: 690) OSL131A ACUUCUAUCAGUGUUUCAGAA[dT][dT](SEQ  OSL131S UUCUGAAACACUGAUAGAAGU[dT][dT] ID NO: 317) (SEQ ID NO: 691) OSL132A UAUUGAUCCGCAGAACUUCUA[dT][dT](SEQ  OSL132S UAGAAGUUCUGCGGAUCAAUA[dT][dT] ID NO: 318) (SEQ ID NO: 692) OSL133A UGUUCUUGGGAUCUACAACAA[dT][dT](SEQ  OSL133S UUGUUGUAGAUCCCAAGAACA[dT][dT] ID NO: 319) (SEQ ID NO: 693) OSL134A AAAGAACGCUCAAUCUUUGGU[dT][dT](SEQ  OSL134S ACCAAAGAUUGAGCGUUCUUU[dT][dT] ID NO: 320) (SEQ ID NO: 694) OSL135A UAAACGUAGCCAUCACUUCGG[dT][dT](SEQ  OSL135S CCGAAGUGAUGGCUACGUUUA[dT][dT] ID NO: 321) (SEQ ID NO: 695) OSL136A AUCUAAAGAAUCAUCAACCCA[dT][dT](SEQ  OSL136S UGGGUUGAUGAUUCUUUAGAU[dT][dT] ID NO: 322) (SEQ ID NO: 696) OSL137A UUAUAUCUAAAGAAUCAUCAA[dT][dT](SEQ  OSL137S UUGAUGAUUCUUUAGAUAUAA[dT][dT] ID NO: 323) (SEQ ID NO: 697) OSL138A AUAGAAUUUUCAAAAACAGUG[dT][dT](SEQ  OSL138S CACUGUUUUUGAAAAUUCUAU[dT][dT] ID NO: 324) (SEQ ID NO: 698) OSL139A UGAUAGAAUUUUCAAAAACAG[dT][dT](SEQ  OSL139S CUGUUUUUGAAAAUUCUAUCA[dT][dT] ID NO: 325) (SEQ ID NO: 699) OSL140A UUUCAAAUUCCUAUCUACCCA[dT][dT](SEQ  OSL140S UGGGUAGAUAGGAAUUUGAAA[dT][dT] ID NO: 326) (SEQ ID NO: 700) OSL141A UUUUCAAAUUCCUAUCUACCC[dT][dT](SEQ  OSL141S GGGUAGAUAGGAAUUUGAAAA[dT][dT] ID NO: 327) (SEQ ID NO: 701) OSL142A AUAUUGUCUCUUAUCACUGUG[dT][dT](SEQ  OSL142S CACAGUGAUAAGAGACAAUAU[dT][dT] ID NO: 328) (SEQ ID NO: 702) OSL143A UGAUAUUGUCUCUUAUCACUG[dT][dT](SEQ  OSL143S CAGUGAUAAGAGACAAUAUCA[dT][dT] ID NO: 329) (SEQ ID NO: 703) OSL144A UGAAAUGGCACAAUUCUUGCC[dT][dT](SEQ  OSL144S GGCAAGAAUUGUGCCAUUUCA[dT][dT] ID NO: 330) (SEQ ID NO: 704) OSL145A UGUUGAAAUGGCACAAUUCUU[dT][dT](SEQ  OSL145S AAGAAUUGUGCCAUUUCAACA[dT][dT] ID NO: 331) (SEQ ID NO: 705) OSL146A AAUUUUCUGUUGAAAUGGCAC[dT][dT](SEQ  OSL146S GUGCCAUUUCAACAGAAAAUU[dT][dT] ID NO: 332) (SEQ ID NO: 706) OSL147A AAAUUUUCUGUUGAAAUGGCA[dT][dT](SEQ  OSL147S UGCCAUUUCAACAGAAAAUUU[dT][dT] ID NO: 333) (SEQ ID NO: 707) OSL148A AUUAGACAAGGCAAAGAUGAG[dT][dT](SEQ  OSL148S CUCAUCUUUGCCUUGUCUAAU[dT][dT] ID NO: 334) (SEQ ID NO: 708) OSL149A ACAUUUAUUGUUUGGAAAGGU[dT][dT](SEQ  OSL149S ACCUUUCCAAACAAUAAAUGU[dT][dT] ID NO: 335) (SEQ ID NO: 709) OSL150A AUCACUUACACUGUCAUAGUC[dT][dT](SEQ  OSL150S GACUAUGACAGUGUAAGUGAU[dT][dT] ID NO: 336) (SEQ ID NO: 710) OSL151A UAGAUUCUAUCACUUACACUG[dT][dT](SEQ  OSL151S CAGUGUAAGUGAUAGAAUCUA[dT][dT] ID NO: 337) (SEQ ID NO: 711) OSL152A AGUAGAUUCUAUCACUUACAC[dT][dT](SEQ  OSL152S GUGUAAGUGAUAGAAUCUACU[dT][dT] ID NO: 338) (SEQ ID NO: 712) OSL153A UUUUGUGUGAAGUAGAUUCUA[dT][dT](SEQ  OSL153S UAGAAUCUACUUCACACAAAA[dT][dT] ID NO: 339) (SEQ ID NO: 713) OSL154A UAAAUUUUGUGUGAAGUAGAU[dT][dT](SEQ  OSL154S AUCUACUUCACACAAAAUUUA[dT][dT] ID NO: 340) (SEQ ID NO: 714) OSL155A UCUAGUAAUCCAGUCAAAGGC[dT][dT](SEQ  OSL155S GCCUUUGACUGGAUUACUAGA[dT][dT] ID NO: 341) (SEQ ID NO: 715) OSL156A AAUUCUUCUAGUAAUCCAGUC[dT][dT](SEQ  OSL156S GACUGGAUUACUAGAAGAAUU[dT][dT] ID NO: 342) (SEQ ID NO: 716) OSL157A UAAAUUCUUCUAGUAAUCCAG[dT][dT](SEQ  OSL157S CUGGAUUACUAGAAGAAUUUA[dT][dT] ID NO: 343) (SEQ ID NO: 717) OSL158A AUAAAUUCUUCUAGUAAUCCA[dT][dT](SEQ  OSL158S UGGAUUACUAGAAGAAUUUAU[dT][dT] ID NO: 344) (SEQ ID NO: 718) OSL159A AUAUACUGGCCAUAGAGAGUC[dT][dT](SEQ  OSL159S GACUCUCUAUGGCCAGUAUAU[dT][dT] ID NO: 345) (SEQ ID NO: 719) OSL160A UUCUUUGUGUGUACAAGUCAG[dT][dT](SEQ  OSL160S CUGACUUGUACACACAAAGAA[dT][dT] ID NO: 346) (SEQ ID NO: 720) OSL161A AAUUCUUUGUGUGUACAAGUC[dT][dT](SEQ  OSL161S GACUUGUACACACAAAGAAUU[dT][dT] ID NO: 347) (SEQ ID NO: 721) OSL162A UCGGUAAAUUCUUUGUGUGUA[dT][dT](SEQ  OSL162S UACACACAAAGAAUUUACCGA[dT][dT] ID NO: 348) (SEQ ID NO: 722) OSL163A UGUUACACUGUUGUUUCUGGU[dT][dT](SEQ  OSL163S ACCAGAAACAACAGUGUAACA[dT][dT] ID NO: 349) (SEQ ID NO: 723) OSL164A AUUGUUACACUGUUGUUUCUG[dT][dT](SEQ  OSL164S CAGAAACAACAGUGUAACAAU[dT][dT] ID NO: 350) (SEQ ID NO: 724) OSL16A5 AAACUGUUCACAAGGAUUGUU[dT][dT](SEQ  OSL165S AACAAUCCUUGUGAACAGUUU[dT][dT] ID NO: 351) (SEQ ID NO: 725) OSL166A ACAUCGUUCACCAUUGUCCAC[dT][dT](SEQ  OSL166S GUGGACAAUGGUGAACGAUGU[dT][dT] ID NO: 352) (SEQ ID NO: 726) OSL167A UGUUAUUGCACAUAAACUCCG[dT][dT](SEQ  OSL167S CGGAGUUUAUGUGCAAUAACA[dT][dT] ID NO: 353) (SEQ ID NO: 727) OSL168A UCUGUUAUUGCACAUAAACUC[dT][dT](SEQ  OSL168S GAGUUUAUGUGCAAUAACAGA[dT][dT] ID NO: 354) (SEQ ID NO: 728) OSL169A UUAUGACAUUUUGUGUAUCCA[dT][dT](SEQ  OSL169S UGGAUACACAAAAUGUCAUAA[dT][dT] ID NO: 355) (SEQ ID NO: 729) OSL170A UGAAUUAUGACAUUUUGUGUA[dT][dT](SEQ  OSL170S UACACAAAAUGUCAUAAUUCA[dT][dT] ID NO: 356) (SEQ ID NO: 730) OSL171A UUUGAAUUAUGACAUUUUGUG[dT][dT](SEQ  OSL171S CACAAAAUGUCAUAAUUCAAA[dT][dT] ID NO: 357) (SEQ ID NO: 731) OSL172A UACAAAUAUUUGAAUUAUGAC[dT][dT](SEQ  OSL172S GUCAUAAUUCAAAUAUUUGUA[dT][dT] ID NO: 358) (SEQ ID NO: 732) OSL173A AAAUAAACGCGAGGAAUACAA[dT][dT](SEQ  OSL173S UUGUAUUCCUCGCGUUUAUUU[dT][dT] ID NO: 359) (SEQ ID NO: 733) OSL174A AAUAAGUAGGGUUUUCAUCAC[dT][dT](SEQ  OSL174S GUGAUGAAAACCCUACUUAUU[dT][dT] ID NO: 360) (SEQ ID NO: 734) OSL175A UCACAAUACCAAUGUUGAGGA[dT][dT](SEQ  OSL175S UCCUCAACAUUGGUAUUGUGA[dT][dT] ID NO: 361) (SEQ ID NO: 735) OSL176A UGUUUCUUGAUCACAAUACCA[dT][dT](SEQ  OSL176S UGGUAUUGUGAUCAAGAAACA[dT][dT] ID NO: 362) (SEQ ID NO: 736) OSL177A AACAAUCUGUUUCUUGAUCAC[dT][dT](SEQ  OSL177S GUGAUCAAGAAACAGAUUGUU[dT][dT] ID NO: 363) (SEQ ID NO: 737) OSL178A UUUACACAGAGAAACUCGGAA[dT][dT](SEQ  OSL178S UUCCGAGUUUCUCUGUGUAAA[dT][dT] ID NO: 364) (SEQ ID NO: 738) OSL179A AUUUACACAGAGAAACUCGGA[dT][dT](SEQ  OSL179S UCCGAGUUUCUCUGUGUAAAU[dT][dT] ID NO: 365) (SEQ ID NO: 739) OSL180A UUCUGAUUCUCAUCGUAGCCG[dT][dT](SEQ  OSL180S CGGCUACGAUGAGAAUCAGAA[dT][dT] ID NO: 366) (SEQ ID NO: 740) OSL181A AUUUUCAGAGCAAGUUCUCCU[dT][dT](SEQ  OSL181S AGGAGAACUUGCUCUGAAAAU[dT][dT] ID NO: 367) (SEQ ID NO: 741) OSL182A AUAUCUUUGGGAUACACAGUC[dT][dT](SEQ  OSL182S GACUGUGUAUCCCAAAGAUAU[dT][dT] ID NO: 368) (SEQ ID NO: 742) OSL183A AGGUAAACUGAUUCUGUUGGC[dT][dT](SEQ  OSL183S GCCAACAGAAUCAGUUUACCU[dT][dT] ID NO: 369) (SEQ ID NO: 743) OSL184A AUAGAAACUGGUUAAGGUGUC[dT][dT](SEQ  OSL184S GACACCUUAACCAGUUUCUAU[dT][dT] ID NO: 370) (SEQ ID NO: 744) OSL185A ACAAUAGAAACUGGUUAAGGU[dT][dT](SEQ  OSL185S ACCUUAACCAGUUUCUAUUGU[dT][dT] ID NO: 371) (SEQ ID NO: 745) OSL186A UCAUCAAUAUCAACACAAGUC[dT][dT](SEQ  OSL186S GACUUGUGUUGAUAUUGAUGA[dT][dT] ID NO: 372) (SEQ ID NO: 746) OSL187A AGAUGUAGGAGCCUAUUACAU[dT][dT](SEQ  OSL187S AUGUAAUAGGCUCCUACAUCU[dT][dT] ID NO: 373) (SEQ ID NO: 747) OSL188A UCGAUGUUACUGUUUUGCCGG[dT][dT](SEQ  OSL188S CCGGCAAAACAGUAACAUCGA[dT][dT] ID NO: 374) (SEQ ID NO: 748) OSL189A UUGCUAAAAAUGAGAUAGGGU[dT][dT](SEQ  OSL189S ACCCUAUCUCAUUUUUAGCAA[dT][dT] ID NO: 375) (SEQ ID NO: 749) OSL190A AUUUCUCAAAUAGUAACGGUU[dT][dT](SEQ  OSL190S AACCGUUACUAUUUGAGAAAU[dT][dT] ID NO: 376) (SEQ ID NO: 750) OSL191A AAUUUCUCAAAUAGUAACGGU[dT][dT](SEQ  OSL191S ACCGUUACUAUUUGAGAAAUU[dT][dT] ID NO: 377) (SEQ ID NO: 751) OSL192A AAAUUUCUCAAAUAGUAACGG[dT][dT](SEQ  OSL192S CCGUUACUAUUUGAGAAAUUU[dT][dT] ID NO: 378) (SEQ ID NO: 752) OSL193A AGUUAAAUUUCUCAAAUAGUA[dT][dT](SEQ  OSL193S UACUAUUUGAGAAAUUUAACU[dT][dT] ID NO: 379) (SEQ ID NO: 753) OSL194A AUCUAUAGUUAAAUUUCUCAA[dT][dT](SEQ  OSL194S UUGAGAAAUUUAACUAUAGAU[dT][dT] ID NO: 380) (SEQ ID NO: 754) OSL195A UAAAAAUAGCCAUCUAUAGUU[dT][dT](SEQ  OSL195S AACUAUAGAUGGCUAUUUUUA[dT][dT] ID NO: 381) (SEQ ID NO: 755) OSL196A AUCUAAUGCCACAACAUUGUC[dT][dT](SEQ  OSL196S GACAAUGUUGUGGCAUUAGAU[dT][dT] ID NO: 382) (SEQ ID NO: 756) OSL197A AAUCCAAUACAAUCUCUUCUC[dT][dT](SEQ  OSL197S GAGAAGAGAUUGUAUUGGAUU[dT][dT] ID NO: 383) (SEQ ID NO: 757) OSL198A ACAUUCUCUCAAUGACUUGCC[dT][dT](SEQ  OSL198S GGCAAGUCAUUGAGAGAAUGU[dT][dT] ID NO: 384) (SEQ ID NO: 758) OSL199A AUGAUUGUCUCCUUGUUUGUC[dT][dT](SEQ  OSL199S GACAAACAAGGAGACAAUCAU[dT][dT] ID NO: 385) (SEQ ID NO: 759) OSL200A AUUAUCACAGACUUGUUGGUU[dT][dT](SEQ  OSL200S AACCAACAAGUCUGUGAUAAU[dT][dT] ID NO: 386) (SEQ ID NO: 760) OSL201A UUCAAAAAUGGUAAUAGCGAA[dT][dT](SEQ  OSL201S UUCGCUAUUACCAUUUUUGAA[dT][dT] ID NO: 387) (SEQ ID NO: 761) OSL202A UCUUCAAAAAUGGUAAUAGCG[dT][dT](SEQ  OSL202S CGCUAUUACCAUUUUUGAAGA[dT][dT] ID NO: 388) (SEQ ID NO: 762) OSL203A AUUUGUUUCCCUUUUCCACUG[dT][dT](SEQ  OSL203S CAGUGGAAAAGGGAAACAAAU[dT][dT] ID NO: 389) (SEQ ID NO: 763) OSL204A AUUUGAUCCAUCAUAUUUGUU[dT][dT](SEQ  OSL204S AACAAAUAUGAUGGAUCAAAU[dT][dT] ID NO: 390) (SEQ ID NO: 764) OSL205A UAUAUGGAUGGUACACAUGGA[dT][dT](SEQ  OSL205S UCCAUGUGUACCAUCCAUAUA[dT][dT] ID NO: 391) (SEQ ID NO: 765) OSL206A AAAGAAGACGGUCUUCAUCAG[dT][dT](SEQ  OSL206S CUGAUGAAGACCGUCUUCUUU[dT][dT] ID NO: 392) (SEQ ID NO: 766) OSL207A UGAAUUCUGUGAAGUUGUCAC[dT][dT](SEQ  OSL207S GUGACAACUUCACAGAAUUCA[dT][dT] ID NO: 393) (SEQ ID NO: 767) OSL208A ACAAUGUCCACUUGUACACUG[dT][dT](SEQ  OSL208S CGGUGUACAAGUGGACAUUGU[dT][dT] ID NO: 394) (SEQ ID NO: 768) OSL209A ACACAAUGUCCACUUGUACAC[dT][dT](SEQ  OSL209S GUGUACAAGUGGACAUUGUGU[dT][dT] ID NO: 395) (SEQ ID NO: 769) OSL210A UUUUUGCAUUCGAACAUAGUA[dT][dT](SEQ  OSL210S UACUAUGUUCGAAUGCAAAAA[dT][dT] ID NO: 396) (SEQ ID NO: 770) OSL211A AUGGUUUUUGCAUUCGAACAU[dT][dT](SEQ  OSL211S AUGUUCGAAUGCAAAAACCAU[dT][dT] ID NO: 397) (SEQ ID NO: 771) OSL212A AUACAAACAUGGUUUUUGCAU[dT][dT](SEQ  OSL212S AUGCAAAAACCAUGUUUGUAU[dT][dT] ID NO: 398) (SEQ ID NO: 772) OSL213A AUCACAUUUCCAAUAUGGCGG[dT][dT](SEQ  OSL213S CCGCCAUAUUGGAAAUGUGAU[dT][dT] ID NO: 399) (SEQ ID NO: 773) OSL214A UGAAGUUCUUCAUCUGAACCA[dT][dT](SEQ  OSL214S UGGUUCAGAUGAAGAACUUCA[dT][dT] ID NO: 400) (SEQ ID NO: 774) OSL215A AUAAAUGCAGCGAUUGUUGUC[dT][dT](SEQ  OSL215S GACAACAAUCGCUGCAUUUAU[dT][dT] ID NO: 401) (SEQ ID NO: 775) OSL216A AUUCUGUACAAGGUUUAGGGG[dT][dT](SEQ  OSL216S CCCCUAAACCUUGUACAGAAU[dT][dT] ID NO: 402) (SEQ ID NO: 776) OSL217A UAUUCUGUACAAGGUUUAGGG[dT][dT](SEQ  OSL217S CCCUAAACCUUGUACAGAAUA[dT][dT] ID NO: 403) (SEQ ID NO: 777) OSL218A AUUCAUAUUCUGUACAAGGUU[dT][dT](SEQ  OSL218S AACCUUGUACAGAAUAUGAAU[dT][dT] ID NO: 404) (SEQ ID NO: 778) OSL219A UAUUCAUAUUCUGUACAAGGU[dT][dT](SEQ  OSL219S ACCUUGUACAGAAUAUGAAUA[dT][dT] ID NO: 405) (SEQ ID NO: 779) OSL220A UUAUAUUCAUAUUCUGUACAA[dT][dT](SEQ  OSL220S UUGUACAGAAUAUGAAUAUAA[dT][dT] ID NO: 406) (SEQ ID NO: 780) OSL221A UAUUGCAACCCAGUUCAUCGG[dT][dT](SEQ  OSL221S CCGAUGAACUGGGUUGCAAUA[dT][dT] ID NO: 407) (SEQ ID NO: 781) OSL222A AUAUUUUCAGCACAUGUUCUU[dT][dT](SEQ  OSL222S AAGAACAUGUGCUGAAAAUAU[dT][dT] ID NO: 408) (SEQ ID NO: 782) OSL223A UUAAUUGGGUACAAUUUUGCU[dT][dT](SEQ  OSL223S AGCAAAAUUGUACCCAAUUAA[dT][dT] ID NO: 409) (SEQ ID NO: 783) OSL224A AAAAACAUUGGUUUCGAACCC[dT][dT](SEQ  OSL224S GGGUUCGAAACCAAUGUUUUU[dT][dT] ID NO: 410) (SEQ ID NO: 784) OSL225A UGUCAAAAACAUUGGUUUCGA[dT][dT](SEQ  OSL225S UCGAAACCAAUGUUUUUGACA[dT][dT] ID NO: 411) (SEQ ID NO: 785) OSL226A UUCGAAUUCGGACAUUGUCAG[dT][dT](SEQ  OSL226S CUGACAAUGUCCGAAUUCGAA[dT][dT] ID NO: 412) (SEQ ID NO: 786) OSL227A AUUAUAUUUUCGAAUUCGGAC[dT][dT](SEQ  OSL227S GUCCGAAUUCGAAAAUAUAAU[dT][dT] ID NO: 413) (SEQ ID NO: 787) OSL228A AGAUUAUAUUUUCGAAUUCGG[dT][dT](SEQ  OSL228S CCGAAUUCGAAAAUAUAAUCU[dT][dT] ID NO: 414) (SEQ ID NO: 788) OSL229A UCAUCUUGAAGAUACUCUGAG[dT][dT](SEQ  OSL229S CUCAGAGUAUCUUCAAGAUGA[dT][dT] ID NO: 415) (SEQ ID NO: 789) OSL230A UAUAUUCCUCAUCUUGAAGAU[dT][dT](SEQ  OSL230S AUCUUCAAGAUGAGGAAUAUA[dT][dT] ID NO: 416) (SEQ ID NO: 790) OSL231A- UUUGAUAGCACCAAACCUAGAGCCC[dT][dT] OSL231S- GGGCUCUAGGUUUGGUGCUAUCAAA[dT] 1 (SEQ ID NO: 417) 1 [dT](SEQ ID NO: 791)  OSL231A- UUUGAUAGCACCAAACCUAGAGCCC[dT]*[dT] OSL231S- GGGCUCUAGGUUUGGUGCUAUCAAA[dT]* 2 (SEQ ID NO: 418) 2 [dT](SEQ ID NO: 792) OSL231A- [mU][mU][mU][mG][mA][mU][mA][mG][mC] OSL231S- [mG][mG][mG][mC][mU][mC][mU][mA] 3 [mA][mC][mC][mA][mA][mA][mC][mC][mU] 3 [mG][mG][mU][mU][mU][mG][mG][mU][mG] [mA][mG][mA][mG][mC][mC][mC][dT]*[dT] [mC][mU][mA][mU][mC][mA][mA][mA]  (SEQ ID NO: 419) [dT]*[dT](SEQ ID NO: 793)  OSL231A- [mU][mU][mU][mG][mA][mU][mA][mG][mC] OSL231S-  [mG][mG][mG][mC][mU][mC][mU][mA]  4 [mA][mC][mC][mA][mA][mA][mC][mC][mU] 4 [mG][mG][mU][mU][mU][mG][mG][mU][mG] [mA][mG][mA][mG][mC][mC][mC][dT]*[dT] [mC][mU][mA][mU][mC][mA][mA][mA] (SEQ ID NO: 420) (SEQ ID NO: 794) OSL231A- [mU][mU][mU][mG][mA][mU][mA][mG][mC] OSL231S- [mG][mG][mG][mC][mU][mC][mU][mA][mG]  5 [mA][mC][mC][mA][mA][mA][mC][mC][mU] 5 [mG][mU][mU][mU][mG][mG][mU][mG] [mA][mG][mA][mG][mC][mC][mC](SEQ ID  [mC][mU][mA][mU][mC][mA][mA][mA]  NO: 421) [dT]*[dT](SEQ ID NO: 795)  OSL231A- [mU][mU][mU][mG][mA][mU][mA][mG][mC] OSL231S- [mG][mG][mG][mC][mU][mC][mU][mA][mG]  6 [mA][mC][mC][mA][mA][mA][mC][mC][mU] 6 [mG][mU][mU][mU][mG][mG][mU][mG] [mA][mG][mA][mG][mC][mC][mC](SEQ ID  [mC][mU][mA][mU][mC][mA][mA][mA] NO: 422) (SEQ ID NO: 796) OSL231A- [mU][mU][mU][mG][mA][mU][mA][mG][mC] OSL231S- GGGCUCUAGGUUUGGUGCUAUCAAA[dT]*  7 [mA][mC][mC][mA][mA][mA][mC][mC][mU] 7 [dT](SEQ ID NO: 797)  [mA][mG][mA][mG][mC][mC][mC][dT]*[dT] (SEQ ID NO: 423) OSL231A- [mU][2fU][mU][2fG][mA][2fU][mA][2fG][mC] OSL231S-  [2fG][mG][2fG][mC][2fU][mC][2fU][mA]  8 [2fA][mC][2fC][mA][2fA][mA][2fC][mC][2fU] 8 [2fG][mG][2fU][mU][2fU][mG][2fG][mU]  [mA][2fG][mA][2fG][mC][2fC][mC][dT]*[dT] [2fG][mC][2fU][mA][2fU][mC][2fA][mA] (SEQ ID NO: 424) [2fA][dT]*[dT](SEQ ID NO: 798)  OSL231A- [mU][2fU][mU][2fG][mA][2fU][mA][2fG][mC] OSL231S-  [2fG][mG][2fG][mC][2fU][mC][2fU][mA]  9 [2fA][mC][2fC][mA][2fA][mA][2fC][mC][2fU] 9 [2fG][mG][2fU][mU][2fU][mG][2fG][mU]  [mA][2fG][mA][2fG][mC][2fC][mC](SEQ ID [2fG][mC][2fU][mA][2fU][mC][2fA][mA] NO: 425) [2fA][dT]*[dT](SEQ ID NO: 799)  OSL231A- [mU][2fU][mU][2fG][mA][2fU][mA][2fG][mC] OSL231S-  [2fG][mG][2fG][mC][2fU][mC][2fU][mA]  10 [2fA][mC][2fC][mA][2fA][mA][2fC][mC][2fU] 10 [2fG][mG][2fU][mU][2fU][mG][2fG][mU] [mA][2fG][mA][2fG][mC][2fC][mC][dT]*[dT] [2fG][mC][2fU][mA][2fU][mC][2fA][mA] (SEQ ID NO: 426) [2fA](SEQ ID NO: 800) OSL231A- [mU][2fU][mU][2fG][mA][2fU][mA][2fG][mC] OSL231S-  [2fG][mG][2fG][mC][2fU][mC][2fU][mA]  11 [2fA][mC][2fC][mA][2fA][mA][2fC][mC][2fU] 11 [2fG][mG][2fU][mU][2fU][mG][2fG][mU] [mA][2fG][mA][2fC][mC][2fC][mC](SEQ ID  [2fG][mC][2fU][mA][2fU][mC][2fA][mA] NO: 427) [2fA](SEQ ID NO: 801) OSL231A- [2fU][mU][2fU][mG][2fA][mU][2fA][mG][2fC] OSL231S-  [mG][2fG][mG][2fC][mU][2fC][mU][2fA]  12 [mA][2fC][mC][2fA][mA][2fA][mC][2fC][mU] 12 [mG][2fG][mU][2fU][mU][2fG][mG][2Fu]  [2fA][mG][2fA][mG][2fC][mC][2fC][dT]*[dT] [mG][2fC][mU][2fA][mU][2fC][mA][2fA] (SEQ ID NO: 428) [mA][dT]*[dT](SEQ ID NO: 802)  OSL231A- [mU][2fA][mU][2fC][mA][2fA][mA][2fC][mC] OSL231S- [2fG][mG][2fG][mC][2fU][mC][2fU][mA]  13 [2fU][mC][2fG][mA][2fU][mA][2fG][mC][2fA] 13 [2fG][mG][2fU][mU][2fU][mG][2fG][mU] [mA][2fC][mA][2fC][mC][2fG][mC](SEQ ID  [2fG][mC][2fU][mA][2fU][mC][2fA][mA] NO: 429) [2fA]-LINKER-LIG(SEQ ID NO: 803) OSL231A- [mU][2fU][2fU][2fG][2fA][2fU][2fA][2fG][2fC] OSL231S-  [2fU][mC][2fU][mA][2fG][mG][2fU][mU]  14 [2fA][2fC][2fC][2fA][2fA][2fA][2fC][2fC][2fU] 14 [2fU][mG][2fG][mU][2fG][mC][2fU][mA]  [2fA][2fG][2fA][2fG][2fC][2fC][2fC][dT]*[dT] [2fU][mC][2fA][mA][2fA][dT]*[dT]    (SEQ ID NO: 430) (SEQ ID NO: 804) OSL231A- [mU][2fU][2fU][2fG][2fA][2fU][2fA][2fG][2fC] OSL231S-  [2fU][mU][2fU][mG][2fG][mU][2fG][mC]  15 [2fA][2fC][2fC][2fA][2fA][2fA][2fC][2fC][2fU] 15 [2fU][mA][2fU][mC][2fA][mA][2fA] [2fA][2fG][2fA][2fG][2fC][2fC][2fC][dT]*[dT] [dT]*[dT](SEQ ID NO: 805) (SEQ ID NO: 431) OSL231A- [mU][2fU][mU][2fG][mA][2fU][mA][2fG][mC] OSL231S- [2fU][mU][2fU][mG][2fG][mU][2fG][mC]  16 [2fA][mC][2fC][mA][2fA][mA][2fC][mC][2fU] 16 [2fU][mA][2fU][mC][2fA][mA][2fA] [mA][2fG][mA][2fG][mC][2fC][mC][dT]*[dT] [dT]*[dT](SEQ ID NO: 806)  (SEQ ID NO: 432) OSL231A- [mU][2fU][mU][2fG][mA][2fU][mA][2fG][C] OSL231S- [2fU][mU][2fU][mG][2fG][mU][2fG][mC]  17 [2fA][mC][2fC][mA][2fA][mA][2fC][mC][2fU] 17 [2fU][mA][2fU][mC][2fA][mA][2fA]   [mA][2fG][mA][2fG][mC](SEQ ID NO: 433)  (SEQ ID NO: 807) OSL231A- [mU][2fU][mU][2fG][mA][2fU][mA][2fG][mC] OSL231S- [2fU][mU][2fU][mG][2fG][mU][2fG][mC]  18 [2fA][mC][2fC][mA][2fA][mA][2fC][2fC][2fU] 18 [2fU][mA][2fU][mC][2fA][mA][2fA]   [2fA][2fG][2fA][2fG][2fC](SEQ ID NO: 434) (SEQ ID NO: 808) OSL232A UCAAAGUUGGGGAUGUAGGCA[dT][dT](SEQ  OSL232S UGCCUACAUCCCCAACUUUGA[dT][dT] ID NO: 435) (SEQ ID NO: 809) OSL233A UCAGUUUCAGGUCAACUUCCU[dT][dT](SEQ  OSL233S AGGAAGUUGACCUGAAACUGA[dT][dT] ID NO: 436) (SEQ ID NO: 810) OSL234A UACGUAUUUCAGUUUCAGGUC[dT][dT](SEQ  OSL234S GACCUGAAACUGAAAUACGUA[dT][dT] ID NO: 437) (SEQ ID NO: 811) OSL235A UUACGUAUUUCAGUUUCAGGU[dT][dT](SEQ  OSL235S ACCUGAAACUGAAAUACGUAA[dT][dT] ID NO: 438) (SEQ ID NO: 812) OSL236A AGUUUAGCCACCUCAAUGCGU[dT][dT](SEQ  OSL236S ACGCAUUGAGGUGGCUAAACU[dT][dT] ID NO: 439) (SEQ ID NO: 813) OSL237A AACAUAAGCCCUAGUUUGGGA[dT][dT](SEQ  OSL237S UCCCAAACUAGGGCUUAUGUU[dT][dT] ID NO: 440) (SEQ ID NO: 814) OSL238A UCGAUUUUAGGUUCCUUUCCC[dT][dT](SEQ  OSL238S GGGAAAGGAACCUAAAAUCGA[dT][dT] ID NO: 441) (SEQ ID NO: 815) OSL239A UCGAAAACCAGGAUGUUGCGG[dT][dT](SEQ  OSL239S CCGCAACAUCCUGGUUUUCGA[dT][dT] ID NO: 442) (SEQ ID NO: 816) OSL240A UCAAAUAAUCGAUAGAAAGGC[dT][dT](SEQ  OSL240S GCCUUUCUAUCGAUUAUUUGA[dT][dT] ID NO: 443) (SEQ ID NO: 817) OSL241A UUGUUCAAAUAAUCGAUAGAA[dT][dT](SEQ  OSL241S UUCUAUCGAUUAUUUGAACAA[dT][dT] ID NO: 444) (SEQ ID NO: 818) OSL242A UUAUGGUUUCAAUAACGUCCU[dT][dT](SEQ  OSL242S AGGACGUUAUUGAAACCAUAA[dT][dT] ID NO: 445) (SEQ ID NO: 819) OSL243A UUUUAUGGUUUCAAUAACGUC[dT][dT](SEQ  OSL243S GACGUUAUUGAAACCAUAAAA[dT][dT] ID NO: 446) (SEQID NO: 820) OSL244A AUUUUAUGGUUUCAAUAACGU[dT][dT](SEQ  OSL244S ACGUUAUUGAAACCAUAAAAU[dT][dT] ID NO: 447) (SEQ ID NO: 821) OSL245A- UUUGCAAUGACUCUCCUAUCAGUCC[dT][dT] OSL245S- GGACUGAUAGGAGAGUCAUUGCAAA[dT] 1 (SEQ ID NO: 448) 1 [dT](SEQ ID NO: 822) OSL245A- UUUGCAAUGACUCUCCUAUCAGUCC[dT]*[dT]  OSL245S- GGACUGAUAGGAGAGUCAUUGCAA]A[dT]* 2 (SEQ ID NO: 449)  2 [dT](SEQ ID NO: 823)  OSL245A- [mU][mU][mU][mG][mC][mA][mA][mU][mG] OSL245S-  [mG][mG][mA][mC][mU][mG][mA][mU][mA]  3 [mA][mC][mU][mC][mU][mC][mC][mU][mA] 3 [mG][mG][mA][mG][mA][mG][mU][mC][mA] [mU][mC][mA][mG][mU][mC][mC][dT]*[dT] [mU][mU][mG][mC][mA][mA][mA][dT]*  (SEQ ID NO: 450) [dT](SEQ ID NO: 824)  OSL245A- [mU][mU][mU][mG][mC][mA][mA][mU][mG] OSL245S- [mG][mG][mA][mC][mU][mG][mA][mU][mA]  4 [mA][mC][mU][mC][mU][mC][mC][mU][mA] 4 [mG][mG][mA][mG][mA][mG][mU][mC][mA] [mU][mC][mA][mG][mU][mC][mC][dT]*[dT] [mU][mU][mG][mC][mA][mA][mA](SEQ  (SEQ ID NO: 451) ID NO: 825) OSL245A- [mU][mU][mU][mG][mC][mA][mA][mU][mG] OSL245S-  [mG][mG][mA][mC][mU][mG][mA][mU]  5 [mA][mC][mU][mC][mU][mC][mC][mU][mA] 5 [mA][mG][mG][mA][mG][mA][mG][mU][mC] [mU][mC][mA][mG][mU][mC][mC](SEQ ID [mA][mU][mU][mG][mC][mA][mA][mA] NO: 452) [dT]*[dT](SEQ ID NO: 826) OSL245A- [mU][mU][mU][mG][mC][mA][mA][mU][mG] OSL245S-  [mG][mG][mA][mC][mU][mG][mA][mU][mA]  6 [mA][mC][mU][mC][mU][mC][mC][mU][mA] 6 [mG][mG][mA][mG][mA][mG][mU][mC][mA] [mU][mC][mA][mG][mU][mC][mC](SEQ ID [mU][mU][mG][mC][mA][mA][mA] NO: 453) (SEQ ID NO: 827) OSL245A- [mU][mU][mU][mG][mC][mA][mA][mU][mG] OSL245S-  GGACUGAUAGGAGAGUCAUUGCAAA[dT]*[dT] 7 [mA][mC][mU][mC][mU][mC][mC][mU][mA] 7 (SEQ ID NO: 828) [mU][mC][mA][mG][mU][mC][mC][dT]*[dT] (SEQ ID NO: 454) OSL245A- [mU][2fU][mU][2fG][mC][2fA][mA][2fU][mG] OSL245S-  [2fG][mG][2fA][mC][2fU][mG][2fA][mU]  8 [2fA][mC][2fU][mC][2fU][mC][2fC][mU][2fA] 8 [2fA][mG][2fG][mA][2fG][mA][2fG][mU] [mU][2fC][mA][2fG][mU][2fC][mC][dT]*[dT] [2fC][mA][2fU][mU][2fG][mC][2fA][mA] (SEQ ID NO: 455) [2fA][dT]*[dT](SEQ ID NO: 829) OSL245A- [mU][2fU][mU][2fG][mC][2fA][mA][2fU][mG] OSL245S- [2fG][mG][2fA][mC][2fU][mG][2fA][mU]  9 [2fA][mC][2fU][mC][2fU][mC][2fC][mU][2fA] 9 [2fA][mG][2fG][mA][2fG][mA][2fG][mU] [mU][2fC][mA][2fG][mU][2fC][mC](SEQ ID  [2fC][mA][2fU][mU][2fG][mC][2fA][mA]  NO: 456) [2fA][dT]*[dT](SEQ ID NO: 830) OSL245A- [mU][2fU][mU][2fG][mC][2fA][mA][2fU][mG] OSL245S-  [2fG][mG][2fA][mC][2fU][mG][2fA][mU]  10 [2fA][mC][2fU][mC][2fU][mC][2fC][mU][2fA] 10 [2fA][mG][2fG][mA][2fG][mA][2fG][mU] [mU][2fC][mA][2fG][mU][2fC][mC][dT]*[dT] [2fC][mA][2fU][mU][2fG][mC][2fA][mA] (SEQ ID NO: 457) [2fA](SEQ ID NO: 831) OSL245A- [mU][2fU][mU][2fG][mC][2fA][mA][2fU][mG] OSL245S-  [2fG][mG][2fA][mC][2fU][mG][2fA][mU]  11 [2fA][mC][2fU][mC][2fU][mC][2fC][mU][2fA] 11 [2fA][mG][2fG][mA][2fG][mA][2fG][mU] [mU][2fC][mA][2fC][mU][2fC][mC] [2fC][mA][2fU][mU][2fG][mC][2fA][mA] (SEQ IDNO: 458) [2fA](SEQ ID NO: 832) OSL245A- [2fU][mU][2fU][mG][2fC][mA][2fA][mU][2fG] OSL245S- [mG][2fG][mA][2fC][mU][2fG][mA][2fU]  12 [mA][2fC][mU][2fC][mU][2fC][mC][2fU][mA] 12 [mA][2fG][mG][2fA][mG][2fA][mG][2fU] [2fU][mC][2fA][mG][2fU][mC][2fC][dT]*[dT] [mC][2fA][mU][2fU][mG][2fC][mA][2fA]  (SEQ ID NO: 459) [mA][dT]*[dT](SEQ ID NO: 833) OSL245A- [mU][2fA][mU][2fC][mC][2fU][mA][2fA][mG] OSL245S-  [2fG][mG][2fA][mC][2fU][mG][2fA][mU]  13 [2fU][mC][2fA][mC][2fA][mC][2fG][mU][2fU] 13 [2fA][mG][2fG][mA][2fG][mA][2fG][mU] [mU][2fG][mA][2fC][mU][2fG][mC](SEQ ID [2fC][mA][2fU][mU][2fG][mC][2fA][mA] NO: 460) [2fA](SEQ ID NO: 834) OSL245A- [mU][2fU][2fU][2fG][2fC][2fA][2fA][2fU] OSL245S-  [2fU][mG][2fA][mU][2fA][mG][2fG][mA]  14 [2fG][2fA][2fC][2fU][2fC][2fU][2fC][2fC] 14 [2fG][mA][2fG][mU][2fC][mA][2fU][mU] [2fU][2fA][2fU][2fC][2fA][2fG][2fU][2fC] [2fG][mC][2fA][mA][2fA][dT]*[dT]   [2fC][dT]*[dT](SEQ ID NO: 461) (SEQ ID NO: 835) OSL245A- [mU][2fU][2fU][2fG][2fC][2fA][2fA][2fU] OSL245S-  [2fG][mA][2fG][mA][2fG][mU][2fC][mA]  15 [2fG][2fA][2fC][2fU][2fC][2fU][2fC][2fC] 15 [2fU][mU][2fG][mC][2fA][mA][2fA] [2fU][2fA][2fU][2fC][2fA][2fG][2fU][2fC] [dT]*[dT](SEQ ID NO: 836) [2fC][dT]*[dT](SEQ ID NO: 462) OSL245A- [mU][2fU][mU][2fG][mC][2fA][mA][2fU][mG] OSL245S-  [2fG][mA][2fG][mA][2fG][mU][2fC][mA]  16 [2fA][mC][2fU][mC][2fU][mC][2fC][mU][2fA] 16 [2fU][mU][2fG][mC][2fA][mA][2fA] [mU][2fC][mA][2fG][mU][2fC][mC][dT]*[dT] [dT]*[dT](SEQ ID NO: 837) (SEQ ID NO: 463) OSL245A- [mU][2fU][mU][2fG][mC][2fA][mA][2fU][mG] OSL245S- [2fG][mA][2fG][mA][2fG][mU][2fC][mA]  17 [2fA][mC][2fU][mC][2fU][mC][2fC][mU][2fA] 17 [2fU][mU][2fG][mC][2fA][mA][2fA]   [mU][2fC][mA][2fG][mU](SEQ ID NO: 464) (SEQ ID NO: 838) OSL245A- [mU][2fU][mU][2fG][mC][2fA][mA][2fU][mG] OSL245S- ACCAGUUAUACUGGAUAUCUA[dT][dT] 18 [2fA][mC][2fU][mC][2fU][mC][2fC][2fU][2fA] 18 (SEQ ID NO: 840) [2fU][2fC][2fA][2fG][2fU](SEQ ID NO: 465) OSL246A UAGAUAUCCAGUAUAACUGGU[dT][dT](SEQ  OSL246S GGGAGAAGUAUGGAAACAAAA[dT][dT] ID NO: 466) (SEQ ID NO: 841) OSL247A UUUUGUUUCCAUACUUCUCCC[dT][dT](SEQ  OSL247S AAGUAUGGAAACAAAAUAAAU[dT][dT] ID NO: 467) (SEQ ID NO: 842) OSL248A AUUUAUUUUGUUUCCAUACUU[dT][dT](SEQ  OSL248S UUCAUCAACUCAGAUACAAUA[dT][dT] ID NO: 468) (SEQ ID NO: 843) OSL249A UAUUGUAUCUGAGUUGAUGAA[dT][dT](SEQ  OSL249S CGGAGGAAAUUGCUAUUUUGA[dT][dT] ID NO: 469) (SEQ ID NO: 844) OSL250A UCAAAAUAGCAAUUUCCUCCG[dT][dT](SEQ  OSL250S AGGAAAUUGCUAUUUUGAUGA[dT][dT] ID NO: 470) (SEQ ID NO: 845) OSL251A UCAUCAAAAUAGCAAUUUCCU[dT][dT](SEQ  OSL251S CACCGGAAAAUAUUGUGAAAU[dT][dT] ID NO: 471) (SEQ ID NO: 846) OSL252A AUUUCACAAUAUUUUCCGGUG[dT][dT](SEQ  OSL252S UUGUGAAAUGGCGUUUUCAAA[dT][dT] ID NO: 472) (SEQ ID NO: 847) 05L253A UUUGAAAACGCCAUUUCACAA[dT][dT](SEQ  OSL253S CAGGAUUCUUCCACUAUAGAA[dT][dT] ID NO: 473) (SEQ ID NO: 848) OSL254A UUCUAUAGUGGAAGAAUCCUG[dT][dT](SEQ  OSL254S GGCAGAUCUUAACAUGGAUAU[dT][dT] ID NO: 474) (SEQ ID NO: 849) OSL255A AUAUCCAUGUUAAGAUCUGCC[dT][dT](SEQ  OSL255S GGCAAUGAGUGAAGACUUUGU[dT][dT] ID NO: 475) (SEQ ID NO: 850) OSL256A ACAAAGUCUUCACUCAUUGCC[dT][dT](SEQ  OSL256S AUCUGAAAAUGUGGAUAAUAA[dT][dT] ID NO: 476) (SEQ ID NO: 851) OSL257A UUAUUAUCCACAUUUUCAGAU[dT][dT](SEQ  OSL257S ACCAGUUAUACUGGAUAUCUA[dT][dT] ID NO: 477) (SEQ ID NO: 840) OSL258A UCUUAUUAUCCACAUUUUCAG[dT][dT](SEQ  OSL258S CUGAAAAUGUGGAUAAUAAGA[dT][dT] ID NO: 478) (SEQ ID NO: 852) OSL259A UCCAUAAUUCUUAUUAUCCAC[dT][dT](SEQ  OSL259S GUGGAUAAUAAGAAUUAUGGA[dT][dT] ID NO: 479) (SEQ ID NO: 853) OSL260A UUCCAUAAUUCUUAUUAUCCA[dT][dT](SEQ  OSL260S UGGAUAAUAAGAAUUAUGGAA[dT][dT] ID NO: 480) (SEQ ID NO: 854) OSL261A UUUUCGUUUGAAGAGAUUCCA[dT][dT](SEQ  OSL261S UGGAAUCUCUUCAAACGAAAA[dT][dT] ID NO: 481) (SEQ ID NO: 855) OSL262A UAGAUUUUCGUUUGAAGAGAU[dT][dT](SEQ  OSL262S AUCUCUUCAAACGAAAAUCUA[dT][dT] ID NO: 482) (SEQ ID NO: 856) OSL263A UUUAGAUUUUCGUUUGAAGAG[dT][dT](SEQ  OSL263S CUCUUCAAACGAAAAUCUAAA[dT][dT] ID NO: 483) (SEQ ID NO: 857) OSL264A UUGUUUAGAUUUUCGUUUGAA[dT][dT](SEQ  OSL264S UUCAAACGAAAAUCUAAACAA[dT][dT] ID NO: 484) (SEQ ID NO: 858) OSL265A UAGUUUGUUUAGAUUUUCGUU[dT][dT] OSL265S AACGAAAAUCUAAACAAACUA[dT][dT] (SEQ ID NO: 485) (SEQ ID NO: 859) 0SL266A UUUCAAAGUUGGUAGUUUGUU[dT][dT](SEQ  OSL266S AACAAACUACCAACUUUGAAA[dT][dT] ID NO: 486) (SEQ ID NO: 860) OSL267A AUUGGAUUUUCAAAGUUGGUA[dT][dT](SEQ  OSL267S UACCAACUUUGAAAAUCCAAU[dT][dT] ID NO: 487) (SEQ ID NO: 861) OSL268A AUAGAUUGGAUUUUCAAAGUU[dT][dT](SEQ  OSL268S AACUUUGAAAAUCCAAUCUAU[dT][dT] ID NO: 488) (SEQ ID NO: 862) OSL269A UUAAAAGUGUCUUCUGUUGCA[dT][dT](SEQ  OSL269S UGCAACAGAAGACACUUUUAA[dT][dT] ID NO: 489) (SEQ ID NO: 863) OSL270A UCUUUAACAAGAUUUGCGGUG[dT][dT](SEQ  OSL270S CACCGCAAAUCUUGUUAAAGA[dT][dT] ID NO: 490) (SEQ ID NO: 864) OSL271A UCUUCUUUAACAAGAUUUGCG[dT][dT](SEQ  OSL271S CGCAAAUCUUGUUAAAGAAGA[dT][dT] ID NO: 491) (SEQ ID NO: 865) OSL272A UGGUAUAGCUAUACUUCAGAG[dT][dT](SEQ  OSL272S CUCUGAAGUAUAGCUAUACCA[dT][dT] ID NO: 492) (SEQ ID NO: 866) OSL273A AUUAUUCCCUAAAUAGCUGGU[dT][dT](SEQ  OSL273S ACCAGCUAUUUAGGGAAUAAU[dT][dT] ID NO: 493) (SEQ ID NO: 867) OSL274A UAAUUAUUCCCUAAAUAGCUG[dT][dT](SEQ  OSL274S CAGCUAUUUAGGGAAUAAUUA[dT][dT] ID NO: 494) (SEQ ID NO: 868) OSL275A AUAUAUGUGCAAAAGUGUGUU[dT][dT](SEQ  OSL275S AACACACUUUUGCACAUAUAU[dT][dT] ID NO: 495) (SEQ ID NO: 869) OSL276A AAAUAUAUGUGCAAAAGUGUG[dT][dT](SEQ  OSL276S CACACUUUUGCACAUAUAUUU[dT][dT] ID NO: 496) (SEQ ID NO: 870) OSL277A AACUUUUUUCAUCUGUUUGUA[dT][dT](SEQ  OSL277S UACAAACAGAUGAAAAAAGUU[dT][dT] ID NO: 497) (SEQ ID NO: 871) OSL278A UAAAGUACUGAAUGUUAACUU[dT][dT](SEQ  OSL278S AAGUUAACAUUCAGUACUUUA[dT][dT] ID NO: 498) (SEQ ID NO: 872) OSL279A UUUUUUUCAUAAAGUACUGAA[dT][dT](SEQ  OSL279S UUCAGUACUUUAUGAAAAAAA[dT][dT] ID NO: 499) (SEQ ID NO: 873) OSL280A UAUUUUUUUCAUAAAGUACUG[dT][dT](SEQ  OSL280S CAGUACUUUAUGAAAAAAAUA[dT][dT] ID NO: 500) (SEQ ID NO: 874) OSL281A AUUUGUAAAAAUAUGAGACGG[dT][dT](SEQ  OSL281S CCGUCUCAUAUUUUUACAAAU[dT][dT] ID NO: 501) (SEQ ID NO: 875) OSL282A ACAUUGUGAUAAUUAUUUGUA[dT][dT](SEQ  OSL282S UACAAAUAAUUAUCACAAUGU[dT][dT] ID NO: 502) (SEQ ID NO: 876) OSL283A AUACAUAUAGUACAUUGUGAU[dT][dT](SEQ  OSL283S AUCACAAUGUACUAUAUGUAU[dT][dT] ID NO: 503) (SEQ ID NO: 877) OSL284A AUAUACAUAUAGUACAUUGUG[dT][dT](SEQ  OSL284S CACAAUGUACUAUAUGUAUAU[dT][dT] ID NO: 504) (SEQ ID NO: 878) OSL285A AAAGAUAUACAUAUAGUACAU[dT][dT](SEQ  OSL285S AUGUACUAUAUGUAUAUCUUU[dT][dT] ID NO: 505) (SEQ ID NO: 879) OSL286A AUUACCUUCAGACAACUUCAG[dT][dT](SEQ  OSL286S CUGAAGUUGUCUGAAGGUAAU[dT][dT] ID NO: 506) (SEQ ID NO: 880) OSL287A UAUUUAUAGUAUUACCUUCAG[dT][dT](SEQ  OSL287S CUGAAGGUAAUACUAUAAAUA[dT][dT] ID NO: 507) (SEQ ID NO: 881) OSL288A UAAUCUUUCCAAAAUUUACAA[dT][dT](SEQ  OSL288S UUGUAAAUUUUGGAAAGAUUA[dT][dT] ID NO: 508) (SEQ ID NO: 882) OSL289A AGUAACAGGAUAAUCUUUCCA[dT][dT](SEQ  OSL289S UGGAAAGAUUAUCCUGUUACU[dT][dT] ID NO: 509) (SEQ ID NO: 883) OSL290A AUUCAGUAACAGGAUAAUCUU[dT][dT](SEQ  OSL290S AAGAUUAUCCUGUUACUGAAU[dT][dT] ID NO: 510) (SEQ ID NO: 884) OSL291A UAGCAAAUUCAGUAACAGGAU[dT][dT](SEQ  OSL291S AUCCUGUUACUGAAUUUGCUA[dT][dT] ID NO: 511) (SEQ ID NO: 885) OSL292A UUAGCAAAUUCAGUAACAGGA[dT][dT](SEQ  OSL292S UCCUGUUACUGAAUUUGCUAA[dT][dT] ID NO: 512) (SEQ ID NO: 886) OSL293A UCUUUAUUAGCAAAUUCAGUA[dT][dT](SEQ  OSL293S UACUGAAUUUGCUAAUAAAGA[dT][dT] ID NO: 513) (SEQ ID NO: 887) OSL294A AUCAUUUACUAUAAUGAUCAC[dT][dT](SEQ  OSL294S GUGAUCAUUAUAGUAAAUGAU[dT][dT] ID NO: 514) (SEQ ID NO: 888) OSL295A UUCUUGUUGGAUCAUUUACUA[dT][dT](SEQ  OSL295S UAGUAAAUGAUCCAACAAGAA[dT][dT] ID NO: 515) (SEQ ID NO: 889) OSL296A UCAAUUCCUUUUCUUGUUGGA[dT][dT](SEQ  OSL296S UCCAACAAGAAAAGGAAUUGA[dT][dT] ID NO: 516) (SEQ ID NO: 890) OSL297A AUUUUAUAGGAAAUAUGAGUG[dT][dT](SEQ  OSL297S CACUCAUAUUUCCUAUAAAAU[dT][dT] ID NO: 517) (SEQ ID NO: 891) OSL298A UAAUUUUAUAGGAAAUAUGAG[dT][dT](SEQ  OSL298S CUCAUAUUUCCUAUAAAAUUA[dT][dT] ID NO: 518) (SEQ ID NO: 892) OSL299A UGCUAAUGUGUAAAAAUGGAC[dT][dT](SEQ  OSL299S GUCCAUUUUUACACAUUAGCA[dT][dT] ID NO: 519) (SEQ ID NO: 893) OSL300A UUGAACAUUAAUUAAGUGCUA[dT][dT](SEQ  OSL300S UAGCACUUAAUUAAUGUUCAA[dT][dT] ID NO: 520) (SEQ ID NO: 894) OSL301A AUUGAACAUUAAUUAAGUGCU[dT][dT](SEQ  OSL301S AGCACUUAAUUAAUGUUCAAU[dT][dT] ID NO: 521) (SEQ ID NO: 895) OSL302A AUAUUGAACAUUAAUUAAGUG[dT][dT](SEQ  OSL302S CACUUAAUUAAUGUUCAAUAU[dT][dT] ID NO: 522) (SEQ ID NO: 896) OSL303A AAAUUGACAUGUAAUAUUGAA[dT][dT](SEQ  OSL303S UUCAAUAUUACAUGUCAAUUU[dT][dT] ID NO: 523) (SEQ ID NO: 897) OSL304A AUCAACAUAGCCAUUAAUCAA[dT][dT](SEQ  OSL304S UUGAUUAAUGGCUAUGUUGAU[dT][dT] ID NO: 524) (SEQ ID NO: 898) OSL305A UCUAUACAACACAUAGUGGCC[dT][dT](SEQ  OSL305S GGCCACUAUGUGUUGUAUAGA[dT][dT] ID NO: 525) (SEQ ID NO: 899) OSL306A AUGUCUAUACAACACAUAGUG[dT][dT](SEQ  OSL306S CACUAUGUGUUGUAUAGACAU[dT][dT] ID NO: 526) (SEQ ID NO: 900) OSL307A ACUGAAUUGCUUUUCCUACCU[dT][dT](SEQ  OSL307S AGGUAGGAAAAGCAAUUCAGU[dT][dT] ID NO: 527) (SEQ ID NO: 901) OSL308A AAAUAAAAAUGUUGUCUUGGC[dT][dT](SEQ  OSL308S GCCAAGACAACAUUUUUAUUU[dT][dT] ID NO: 528) (SEQ ID NO: 902) OSL309A AUCACAAAUAAAAAUGUUGUC[dT][dT](SEQ  OSL309S GACAACAUUUUUAUUUGUGAU[dT][dT] ID NO: 529) (SEQ ID NO: 903) OSL310A AAUGAUAUGGGAUUUCCUCAU[dT][dT](SEQ  OSL310S AUGAGGAAAUCCCAUAUCAUU[dT][dT] ID NO: 530) (SEQ ID NO: 904) OSL311A AUUAACCACAAACUCAAUGCA[dT][dT](SEQ  OSL311S UGCAUUGAGUUUGUGGUUAAU[dT][dT] ID NO: 531) (SEQ ID NO: 905) OSL312A UUUAAUUAACCACAAACUCAA[dT][dT](SEQ  OSL312S UUGAGUUUGUGGUUAAUUAAA[dT][dT] ID NO: 532) (SEQ ID NO: 906) OSL313A UUUGGUUUCAGAAAUUCAGCU[dT][dT](SEQ  OSL313S AGCUGAAUUUCUGAAACCAAA[dT][dT] ID NO: 533) (SEQ ID NO: 907) OSL314A UUAUGAAGACACAGAUUUGGU[dT][dT](SEQ  OSL314S ACCAAAUCUGUGUCUCAUAA[dT][dT] ID NO: 534) (SEQ ID NO: 908) OSL315A UUUCAUAGAAACAAAAACCCA[dT][dT](SEQ  OSL315S UGGGUUUUUGUUUCUAUGAAA[dT][dT] ID NO: 535) (SEQ ID NO: 909) OSL316A AUGAUAUUUUCAUAGAAACAA[dT][dT](SEQ  OSL316S UUGUUUCUAUGAAAAUAUCAU[dT][dT] ID NO: 536) (SEQ ID NO: 910) OSL317A UAUAAUGAUAUUUUCAUAGAA[dT][dT](SEQ  OSL317S UUCUAUGAAAAUAUCAUUAUA[dT][dT] ID NO: 537) (SEQ ID NO: 911) OSL318A UGAUUAUAAUGAUAUUUUCAU[dT][dT](SEQ  OSL318S AUGAAAAUAUCAUUAUAAUCA[dT][dT] ID NO: 538) (SEQ ID NO: 912) OSL319A AUAAAUAGUGAUUAUAAUGAU[dT][dT](SEQ  OSL319S AUCAUUAUAAUCACUAUUUAU[dT][dT] ID NO: 539) (SEQ ID NO: 913) OSL320A AAAAGCUUAAUAAGAAUGGUU[dT][dT](SEQ  OSL320S AACCAUUCUUAUUAAGCUUUU[dT][dT] ID NO: 540) (SEQ ID NO: 914) OSL321A AAAAAGCUUAAUAAGAAUGGU[dT][dT](SEQ  OSL321S ACCAUUCUUAUUAAGCUUUUU[dT][dT] ID NO: 541) (SEQ ID NO: 915) OSL322A UAAAUGUACACAUUUAGCCAC[dT][dT](SEQ  OSL322S GUGGCUAAAUGUGUACAUUUA[dT][dT] ID NO: 542) (SEQ ID NO: 916) OSL323A AUAAAUGUACACAUUUAGCCA[dT][dT](SEQ  OSL323S UGGCUAAAUGUGUACAUUUAU[dT][dT] ID NO: 543) (SEQ ID NO: 917) OSL324A UAUAAAUGUACACAUUUAGCC[dT][dT](SEQ  OSL324S GGCUAAAUGUGUACAUUUAUA[dT][dT] ID NO: 544) (SEQ ID NO: 918) OSL325A UUCUAAUAUAAAUGUACACAU[dT][dT](SEQ  OSL325S AUGUGUACAUUUAUAUUAGAA[dT][dT] ID NO: 545) (SEQ ID NO: 919) OSL326A AAGAAUUAAAGAAAAGAUCUG[dT][dT](SEQ  OSL326S CAGAUCUUUUCUUUAAUUCUU[dT][dT] ID NO: 546) (SEQ ID NO: 920) OSL327A AAUAAGAAUUAAAGAAAAGAU[dT][dT](SEQ  OSL327S AUCUUUUCUUUAAUUCUUAUU[dT][dT] ID NO: 547) (SEQ ID NO: 921) OSL328A AAACCAAUAAGAAUUAAAGAA[dT][dT](SEQ  OSL328S UUCUUUAAUUCUUAUUGGUUU[dT][dT] ID NO: 548) (SEQ ID NO: 922) OSL329A ACUAUACCCACUAUUUAAGAG[dT][dT](SEQ  OSL329S CUCUUAAAUAGUGGGUAUAGU[dT][dT] ID NO: 549) (SEQ ID NO: 923) OSL330A ACAAAUGUGCAAUAUUAGCAC[dT][dT](SEQ  OSL330S GUGCUAAUAUUGCACAUUUGU[dT][dT] ID NO: 550) (SEQ ID NO: 924) OSL331A AACAAAUGUGCAAUAUUAGCA[dT][dT](SEQ  OSL331S UGCUAAUAUUGCACAUUUGUU[dT][dT] ID NO: 551) (SEQ ID NO: 925) OSL332A AUGUUUCAUUCAUUCAUCCAU[dT][dT](SEQ  OSL332S AUGGAUGAAUGAAUGAAACAU[dT][dT] ID NO: 552) (SEQ ID NO: 926) OSL333A AGUAGUAUAUGUUUCAUUCAU[dT][dT](SEQ  OSL333S AUGAAUGAAACAUAUACUACU[dT][dT] ID NO: 553) (SEQ ID NO: 927) OSL334A AAUCAGUAGUAUAUGUUUCAU[dT][dT](SEQ  OSL334S AUGAAACAUAUACUACUGAUU[dT][dT] ID NO: 554) (SEQ ID NO: 928) OSL335A AAAUAAUCAGUAGUAUAUGUU[dT][dT](SEQ  OSL335S AACAUAUACUACUGAUUAUUU[dT][dT] ID NO: 555) (SEQ ID NO: 929) OSL336A AAUCAAAGUAAUUACAGUCAG[dT][dT](SEQ  OSL336S CUGACUGUAAUUACUUUGAUU[dT][dT] ID NO: 556) (SEQ ID NO: 930) OSL337A AUCUAAUCAAAGUAAUUACAG[dT][dT](SEQ  OSL337S CUGUAAUUACUUUGAUUAGAU[dT][dT] ID NO: 557) (SEQ ID NO: 931) OSL338A UUAUUUCCAGUUGUUUAUCUA[dT][dT](SEQ  OSL338S UAGAUAAACAACUGGAAAUAA[dT][dT] ID NO: 558) (SEQ ID NO: 932) OSL339A UUAUUAGAACUUUUUCAGCAG[dT][dT](SEQ  OSL339S CUGCUGAAAAAGUUCUAAUAA[dT][dT] ID NO: 559) (SEQ ID NO: 933) OSL340A UUUAUUAGAACUUUUUCAGCA[dT][dT](SEQ  OSL340S UGCUGAAAAAGUUCUAAUAAA[dT][dT] ID NO: 560) (SEQ ID NO: 934)

TABLE 5A CD320 ANTISENSE TARGET start SEQ target posi- ID ID position tion target sequence Location Size NO: OSC1    2-24    2 TGCGCGTGCGCAGGGATAAGAGA 5′ UTR  21  996 OSC2    4-26    4 CGCGTGCGCAGGGATAAGAGAGC 5′ UTR 21  997 OSC3   48-70   48 GCGCCGCTGTGGGGACAGCATGA 5′ UTR 21  998 OSC4   63-85   63 CAGCATGAGCGGCGGTTGGATGG 5′ UTR- 21  999 CDS OSC5  164-186  164 CCGCCGCGAGCCCGCTTTCCACC CDS 21 1000 OSC6  222-244  222 CTCGTGCCCACCCACCAAGTTCC CDS 21 1001 OSC7  225-247  225 GTGCCCACCCACCAAGTTCCAGT CDS 21 1002 OSC8  227-249  227 GCCCACCCACCAAGTTCCAGTGC CDS 21 1003 OSC9  244-266  244 CAGTGCCGCACCAGTGGCTTATG CDS 21 1004 OSC10  249-271  249 CCGCACCAGTGGCTTATGCGTGC CDS 21 1005 OSC11  282-304  282 GCGCTGCGACAGGGACTTGGACT CDS 21 1006 OSC12  306-328  306 CAGCGATGGCAGCGATGAGGAGG CDS 21 1007 OSC13  390-412  390 CCCCTGCACCGGCGTCAGTGACT CDS 21 1008 OSC14  411-433  411 CTGCTCTGGGGGAACTGACAAGA CDS 21 1009 OSC15  414-436  414 CTCTGGGGGAACTGACAAGAAAC CDS 21 1010 OSC16  417-439  417 TGGGGGAACTGACAAGAAACTGC CDS 21 1011 OSC17  422-466  422 GAACTGACAAGAAACTGCGCAACTG CDS 25 1012 OSC18  483-505  483 CACGCTGAGCGATGACTGCATTC CDS 21 1013 OSC19  484-506  484 ACGCTGAGCGATGACTGCATTCC CDS 21 1014 OSC20  487-509  487 CTGAGCGATGACTGCATTCCACT CDS 21 1015 OSC21  489-511  489 GAGCGATGACTGCATTCCACTCA CDS 21 1016 OSC22  520-542  520 TGCGACGGCCACCCAGACTGTCC CDS 21 1017 OSC23  556-578  556 GAGCTCGGCTGTGGAACCAATGA CDS 21 1018 OSC24  560-582  560 TCGGCTGTGGAACCAATGAGATC CDS 21 1019 OSC25  561-583  561 CGGCTGTGGAACCAATGAGATCC CDS 21 1020 OSC26  564-586  564 CTGTGGAACCAATGAGATCCTCC CDS 21 1021 OSC27  626-648  626 TGGAGAGTGTCACCTCTCTCAGG CDS 21 1022 OSC28  641-663  641 CTCTCAGGAATGCCACAACCATG CDS 21 1023 OSC29  689-711  689 TCCCCTCTGTCGGGAATGCCACA CDS 21 1024 OSC30  695-717  695 CTGTCGGGAATGCCACATCCTCC CDS 21 1025 OSC31  719-741  719 CTGCCGGAGACCAGTCTGGAAGC CDS 21 1026 OSC32  741-763  741 CCCAACTGCCTATGGGGTTATTG CDS 21 1027 OSC33  767-789  767 CTGCTGCGGTGCTCAGTGCAAGC CDS 21 1028 OSC34  795-817  795 CACCGCCACCCTCCTCCTTTTGT CDS 21 1029 OSC35  797-819  797 CCGCCACCCTCCTCCTTTTGTCC CDS 21 1030 OSC36  843-865  843 CCGCCCACTGGGGTTACTGGTGG CDS 21 1031 OSC37  852-874  852 GGGGTTACTGGTGGCCATGAAGG CDS 21 1032 OSC38  857-879  857 TACTGGTGGCCATGAAGGAGTCC CDS 21 1033 OSC39  874-896  874 GAGTCCCTGCTGCTGTCAGAACA CDS 21 1034 OSC40  878-900  878 CCCTGCTGCTGTCAGAACAGAAG CDS 21 1035 OSC41  881-903  881 TGCTGCTGTCAGAACAGAAGACC CDS 21 1036 OSC42  884-906  884 TGCTGTCAGAACAGAAGACCTCG CDS 21 1037 OSC43  901-923  901 ACCTCGCTGCCCTGAGGACAAGC CDS 21 1038 OSC44  907-929  907 CTGCCCTGAGGACAAGCACTTGC CDS- 21 1039   3′ UTR OSC45  971-993  971 GAGCAGTGATGCGGATGGGTACC 3′ UTR 21 1040 OSC46  995-  995 GGGCACACCAGCCCTCAGAGACC 3′ UTR 21 1041 1017 OSC47 1006- 1006 CCCTCAGAGACCTGAGCTCTT 3′ UTR 21 1393 1026 OSC48 1006- 1006 CCCTCAGAGACCTGAGCTCTTCT 3′ UTR 21 1042 1028 OSC49 1008- 1008 CTCAGAGACCTGAGCTCTTCTGG 3′ UTR 21 1043 1030 OSC50 1082- 1082 GGGTCCCTGGACACTCCCTATGG 3′ UTR 21 1044 1104 OSC51 1085- 1085 TCCCTGGACACTCCCTATGGAGA 3′ UTR 21 1045 1107 OSC52 1088- 1088 CTGGACACTCCCTATGGAGATCC 3′ UTR 21 1046 1110 OSC53 1129- 1129 ACCTGCCACAGCCAGAACTGAGG 3′ UTR 21 1047 1151 OSC54 1163- 1163 GGCAGCTCCCAGGGGGTAGAACG 3′ UTR 21 1048 1185 OSC55 1176- 1176 GGGTAGAACGGCCCTGTGCTTAA 3′ UTR 21 1049 1198 OSC56 1182- 1182 AACGGCCCTGTGCTTAAGACACT 3′ UTR 21 1050 1204 OSC57 1184- 1184 CGGCCCTGTGCTTAAGACACTCC 3′ UTR 21 1051 1206 OSC58 1237- 1237 TTGCTTCACATCCTCAAAAAAAA 3′ UTR 21 1052 1259 OSC59 1238- 1238 TGCTTCACATCCTCAAAAAAAAA 3′ UTR 21 1053 1260

TABLE 6A LRP2 ANTISENSE TARGET Target Start SEQ posi- posi- Loca- ID ID tion tion Target sequence tion Size NO: OSL1 512-534   512 GTCAAGATTGCTCACAAAGTACA CDS 21 1054 OSL2 566-588   566 GTCAGTGTATCCCAAGTGAATAC CDS 21 1055 OSL3 763-785   763 TTGCACAATGAGTTTTCATGTGG CDS 21 1056 OSL4 939-961   939 TGGAGAAGATGACTGTAAAGATA CDS 21 1057 OSL5 941-963   941 GAGAAGATGACTGTAAAGATAAT CDS 21 1058 OSL6 992-   992 CTCATGATGTTCATAAATGTTCC CDS 21 1059 1014 OSL7 1053-  1053 CTCCATTTATAAAGTTTGTGATG CDS 21 1060 1075 OSL8 1054-  1054 TCCATTTATAAAGTTTGTGATGG CDS 21 1061 1076 OSL9 1119-  1119 TACCGGAAAATACTGTAGTATGA CDS 21 1062 1141 OSL10 1121-  1121 CCGGAAAATACTGTAGTATGACT CDS 21 1063 1143 OSL11 1267-  1267 TGCCAGATATGGGGAATTTGTGA CDS 21 1064 1289 OSL12 1329-  1329 CTGTGAAGAAGGGTATATCTTGG CDS 21 1065 1351 OSL13 1356-  1356 TGGACAGTATTGCAAAGCTAATG CDS 21 1066 1378 OSL14 1360-  1360 CAGTATTGCAAAGCTAATGATTC CDS 21 1067 1382 OSL15 1366-  1366 TGCAAAGCTAATGATTCCTTTGG CDS 21 1068 1388 OSL16 1423-  1423 TTGTTAATTGGTGATATTCATGG CDS 21 1069 1445 OSL17 1541-  1541 CCGTGCAAAATAAGGTTTTTTCA CDS 21 1070 1563 OSL18 1543-  1543 GTGCAAAATAAGGTTTTTTCAGT CDS 21 1071 1565 OSL19 1552-  1552 AAGGTTTTTTCAGTTGACATTAA CDS 21 1072 1574 OSL20 1553-  1553 AGGTTTTTTCAGTTGACATTAAT CDS 21 1073 1575 OSL21 1562-  1562 CAGTTGACATTAATGGTTTAAAT CDS 21 1074 1584 OSL22 1565-  1565 TTGACATTAATGGTTTAAATATC CDS 21 1075 1587 OSL23 1638-  1638 CTGGGTTAATAATAAAATCTATC CDS 21 1076 1660 OSL24 1639-  1639 TGGGTTAATAATAAAATCTATCT CDS 21 1077 1661 OSL25 1680-  1680 CCGCATAGATATGGTAAATTTGG CDS 21 1078 1702 OSL26 1719-  1719 TACCCTTATAACTGAAAACTTGG CDS 21 1079 1741 OSL27 1767-  1767 CCCAACTGTTGGTTATTTATTTT CDS 21 1080 1789 OSL28 1772-  1772 CTGTTGGTTATTTATTTTTCTCA CDS 21 1081 1794 OSL29 1895-  1895 GGGTAACTCTGGATATGATATCG CDS 21 1082 1917 OSL30 1942-  1942 CGGTTTGATTACATTGAAACTGT CDS 21 1083 1964 OSL31 1946-  1946 TTGATTACATTGAAACTGTAACT CDS 21 1084 1968 OSL32 1951-  1951 TACATTGAAACTGTAACTTATGA CDS 21 1085 1973 OSL33 2187-  2187 TGCTACCAATCCGTGTAAAGATA CDS 21 1086 2209 OSL34 2437-  2437 TTCTTTGTCGGGATTGATTTTGA CDS 21 1087 2459 OSL35 2469-  2469 CAGCACTATCTTTTTTTCAGATA CDS 21 1088 2491 OSL36 2470-  2470 AGCACTATCTTTTTTTCAGATAT CDS 21 1089 2492 OSL37 2491-  2491 ATGTCAAAACACATGATTTTTAA CDS 21 1090 2513 OSL38 2498-  2498 AACACATGATTTTTAAGCAAAAG CDS 21 1091 2520 OSL39 2558-  2558 GGGTGGAAAATGTTGAAAGTTTG CDS 21 1092 2580 OSL40 2579-  2579 TGGCTTTTGATTGGATTTCAAAG CDS 21 1093 2601 OSL41 2580-  2580 GGCTTTTGATTGGATTTCAAAGA CDS 21 1094 2602 OSL42 2589-  2589 TTGGATTTCAAAGAATCTCTATT CDS 21 1095 2611 OSL43 2590-  2590 TGGATTTCAAAGAATCTCTATTG CDS 21 1096 2612 OSL44 2670-  2670 CACAGTAGTTCAGTATTTAAATA CDS 21 1097 2692 OSL45 2672-  2672 CAGTAGTTCAGTATTTAAATAAC CDS 21 1098 2694 OSL46 2714-  2714 ATCCTTTTGCCGGGTATCTATTC CDS 21 1099 2736 OSL47 2800-  2800 CCTGTAATAAACACTACTCTT CDS 21 1394 2820 OSL48 2869-  2869 TGGGTAGATGCCTATTTTGATAA CDS 21 1100 2891 OSL49 2877-  2877 TGCCTATTTTGATAAAATTGAGC CDS 21 1101 2899 OSL50 2971-  2971 GCCATCTTTGGAGAGCATTTATT CDS 21 1102 2993 OSL51 3074-  3074 TTGCTTACATACTGCATTTGAAA CDS 21 1103 3096 OSL52 3075-  3075 TGCTTACATACTGCATTTGAAAT CDS 21 1104 3097 OSL53 3120-  3120 TGGTTCTAACGCCTGTAATCAAC CDS 21 1105 3142 OSL54 3356-  3356 TCGATGATTGTCATGATAACAGT CDS 21 1106 3378 OSL55 3546-  3546 CACCCAATACACCTGTGATAATC CDS 21 1107 3568 OSL56 3547-  3547 ACCCAATACACCTGTGATAATCA CDS 21 1108 3569 OSL57 3569-  3569 ACCAGTGTATCTCAAAGAACTGG CDS 21 1109 3591 OSL58 3629-  3629 ATGAAAAGAACTGCAATTCGACA CDS 21 1110 3651 OSL59 3681-  3681 CCCCAATCATCGATGTATTGACC CDS 21 1111 3703 OSL60 3690-  3690 TCGATGTATTGACCTATCGTTTG CDS 21 1112 3712 OSL61 3693-  3693 ATGTATTGACCTATCGTTTGTCT CDS 21 1113 3715 OSL62 3828-  3828 TCGTTGTGATGGTGTTTTTGATT CDS 21 1114 3850 OSL63 3945-  3945 CCCGAACTTCTGGGAATGTGATG CDS 21 1115 3967 OSL64 3946-  3946 CCGAACTTCTGGGAATGTGATGG CDS 21 1116 3968 OSL65 4015-  4015 CCCAAGACTTGCCCTTCATCATA CDS 21 1117 4037 OSL66 4348-  4348 TTCTTACTTGCCAATGATTCTAA CDS 21 1118 4370 OSL67 4379-  4379 AAGACATAGATGAATGTGATATT CDS 21 1119 4401 OSL68 4381-  4381 GACATAGATGAATGTGATATTCT CDS 21 1120 4403 OSL69 4455-  4455 GTGTGATACAGGCTACATGTTAG CDS 21 1121 4477 OSL70 4464-  4464 AGGCTACATGTTAGAAAGTGATG CDS 21 1122 4486 OSL71 4465-  4465 GGCTACATGTTAGAAAGTGATGG CDS 21 1123 4487 OSL72 4597-  4597 GTCGAGAATGGTTCTTACATTGT CDS 21 1124 4619 OSL73 4600-  4600 GAGAATGGTTCTTACATTGTAGC CDS 21 1125 4622 OSL74 4612-  4612 TACATTGTAGCTGTTGATTTTGA CDS 21 1126 4634 OSL75 4620-  4620 AGCTGTTGATTTTGATTCAATTA CDS 21 1127 4642 OSL76 4622-  4622 CTGTTGATTTTGATTCAATTAGT CDS 21 1128 4644 OSL77 4635-  4635 TTCAATTAGTGGTCGTATCTTTT CDS 21 1129 4657 OSL78 4732-  4732 AGCATCATCTTGACTGAAACTAT CDS 21 1130 4754 OSL79 4735-  4735 ATCATCTTGACTGAAACTATTGC CDS 21 1131 4757 OSL80 4741-  4741 TTGACTGAAACTATTGCAATAGA CDS 21 1132 4763 OSL81 4743-  4743 GACTGAAACTATTGCAATAGATT CDS 21 1133 4765 OSL82 4745-  4745 CTGAAACTATTGCAATAGATTGG CDS 21 1134 4767 OSL83 4806-  4806 AACAATTGAAGTCTCCAAAATTG CDS 21 1135 4828 OSL84 4847-  4847 TGCTGATTAGTAAAAACCTAACA CDS 21 1136 4869 OSL85 4883-  4883 TAGCATTAGATCCCAGAATGAAT CDS 21 1137 4905 OSL86 4884-  4884 AGCATTAGATCCCAGAATGAATG CDS 21 1138 4906 OSL87 4896-  4896 CAGAATGAATGAGCATCTACTGT CDS 21 1139 4918 OSL88 5077-  5077 ATGGACTTTTGTGATTATAATGG CDS 21 1140 5099 OSL89 5080-  5080 GACTTTTGTGATTATAATGGACA CDS 21 1141 5102 OSL90 5126-  5126 GTGATTTGATTATACGGCA CDS 19 1142 5144 OSL91 5241-  5241 GTCAGTTGTAATGTATAATATTC CDS 21 1143 5263 OSL92 5246-  5246 TTGTAATGTATAATATTCAATGG CDS 21 1144 5268 OSL93 5291-  5291 ATCCTTCGAAACAACCAAATTCC CDS 21 1145 5313 OSL94 5295-  5295 TTCGAAACAACCAAATTCCGTGA CDS 21 1146 5317 OSL95 5447-  5447 AACCTTTCTTAATAACTGTAAGG CDS 21 1147 5469 OSL96 5467-  5467 AGGCAACATATAATTTTTGGAAT CDS 21 1148 5489 OSL97 5468-  5468 GGCAACATATAATTTTTGGAATC CDS 21 1149 5490 OSL98 5538-  5538 AGGGATACAGAATGGTTTAGATG CDS 21 1150 5560 OSL99 5539-  5539 GGGATACAGAATGGTTTAGATGT CDS 21 1151 5561 OSL100 5545-  5545 CAGAATGGTTTAGATGTTGAATT CDS 21 1152 5567 OSL101 5584-  5584 TACATCTATTGGGTTGAAAATCC CDS 21 1153 5606 OSL102 5644-  5644 AGGACAGTATTTGCTTCTATATC CDS 21 1154 5666 OSL103 5648-  5648 CAGTATTTGCTTCTATATCTATG CDS 21 1155 5670 OSL104 5677-  5677 CCTTCTATGAACCTGGCCTTA CDS 21 1156 5697 OSL105 5692-  5692 GCCTTAGATTGGATTTCAAGAAA CDS 21 1157 5714 OSL106 5701-  5701 TGGATTTCAAGAAACCTTTATTC CDS 21 1158 5723 OSL107 5738-  5738 CTCAGTCAATCGAGGTTTTGACA CDS 21 1159 5760 OSL108 5765-  5765 ACGGAGATATCAGATACAGAAAA CDS 21 1160 5787 OSL109 5766-  5766 CGGAGATATCAGATACAGAAAAA CDS 21 1161 5788 OSL110 5768-  5768 GAGATATCAGATACAGAAAAACA CDS 21 1162 5790 OSL111 5775-  5775 CAGATACAGAAAAACATTGATTG CDS 21 1163 5797 OSL112 6115-  6115 GTCCATGATTCTTTCCTTTATTA CDS 21 1164 6137 OSL113 6116-  6116 TCCATGATTCTTTCCTTTATTAT CDS 21 1165 6138 OSL114 6123-  6123 TTCTTTCCTTTATTATACTGATG CDS 21 1166 6145 OSL115 6146-  6146 AACAGTATGAGGTCATTGAAAGA CDS 21 1167 6168 OSL116 6202-  6202 TTGAGAGATAATGTTCCAAATCT CDS 21 1168 6224 OSL117 6204-  6204 GAGAGATAATGTTCCAAATCTGA CDS 21 1169 6226 OSL118 6206-  6206 GAGATAATGTTCCAAATCTGAGG CDS 21 1170 6228 OSL119 6266-  6266 CCTCAAATGGCTGTAGCAA CDS 19 1171 6284 OSL120 6387-  6387 CTCTCCATATAACTCTTTCATTG CDS 21 1172 6409 OSL121 6390-  6390 TCCATATAACTCTTTCATTGTTG CDS 21 1173 6412 OSL122 6397-  6397 AACTCTTTCATTGTTGTTTCAAT CDS 21 1174 6419 OSL123 6399-  6399 CTCTTTCATTGTTGTTTCAATGC CDS 21 1175 6421 OSL124 6425-  6425 CTGCAATCAGAGGCTTTAGCTTG CDS 21 1176 6447 OSL125 6426-  6426 TGCAATCAGAGGCTTTAGCTTGG CDS 21 1177 6448 OSL126 6434-  6434 GAGGCTTTAGCTTGGAATTGTCA CDS 21 1178 6456 OSL127 6436-  6436 GGCTTTAGCTTGGAATTGTCAGA CDS 21 1179 6458 OSL128 6445-  6445 TTGGAATTGTCAGATCATTCAGA CDS 21 1180 6467 OSL129 6603-  6603 TGGATCTTCTCTGATGAACATTG CDS 21 1181 6625 OSL130 6619-  6619 AACATTGTGACACATGGAATAGG CDS 21 1182 6641 OSL131 6711-  6711 TTCTGAAACACTGATAGAAGTTC CDS 21 1183 6733 OSL132 6725-  6725 TAGAAGTTCTGCGGATCAATACT CDS 21 1184 6747 OSL133 6797-  6797 TTGTTGTAGATCCCAAGAACAGA CDS 21 1185 6819 OSL134 6849-  6849 ACCAAAGATTGAGCGTTCTTTCC CDS 21 1186 6871 OSL135 6939-  6939 CCGAAGTGATGGCTACGTTTATT CDS 21 1187 6961 OSL136 6961-  6961 TGGGTTGATGATTCTTTAGATAT CDS 21 1188 6983 OSL137 6965-  6965 TTGATGATTCTTTAGATATAATT CDS 21 1189 6987 OSL138 7062-  7062 CACTGTTTTTGAAAATTCTATCA CDS 21 1190 7084 OSL139 7064-  7064 CTGTTTTTGAAAATTCTATCATA CDS 21 1191 7086 OSL140 7087-  7087 TGGGTAGATAGGAATTTGAAAAA CDS 21 1192 7109 OSL141 7088-  7088 GGGTAGATAGGAATTTGAAAAAG CDS 21 1193 7110 OSL142 7152-  7152 CACAGTGATAAGAGACAATATCA CDS 21 1194 7174 OSL143 7154-  7154 CAGTGATAAGAGACAATATCAAC CDS 21 1195 7176 OSL144 7348-  7348 GGCAAGAATTGTGCCATTTCAAC CDS 21 1196 7370 OSL145 7351-  7351 AAGAATTGTGCCATTTCAACAGA CDS 21 1197 7373 OSL146 7358-  7358 GTGCCATTTCAACAGAAAATTTC CDS 21 1198 7380 OSL147 7359-  7359 TGCCATTTCAACAGAAAATTTCC CDS 21 ligg 7381 OSL148 7381-  7381 CTCATCTTTGCCTTGTCTAATTC CDS 21 1200 7403 OSL149 7443-  7443 ACCTTTCCAAACAATAAATGTGG CDS 21 1201 7465 OSL150 7486-  7486 GACTATGACAGTGTAAGTGATAG CDS 21 1202 7508 OSL151 7494-  7494 CAGTGTAAGTGATAGAATCTACT CDS 21 1203 7516 OSL152 7496-  7496 GTGTAAGTGATAGAATCTACTTC CDS 21 1204 7518 OSL153 7506-  7506 TAGAATCTACTTCACACAAAATT CDS 21 1205 7528 OSL154 7510-  7510 ATCTACTTCACACAAAATTTAGC CDS 21 1206 7532 OSL155 7627-  7627 GCCTTTGACTGGATTACTAGAAG CDS 21 1207 7649 OSL156 7633-  7633 GACTGGATTACTAGAAGAATTTA CDS 21 1208 7655 OSL157 7635-  7635 CTGGATTACTAGAAGAATTTATT CDS 21 1209 7657 OSL158 7636-  7636 TGGATTACTAGAAGAATTTATTA CDS 21 1210 7658 OSL159 8007-  8007 GACTCTCTATGGCCAGTATATTT CDS 21 1211 8029 OSL160 8036-  8036 CTGACTTGTACACACAAAGAATT CDS 21 1212 8058 OSL161 8038-  8038 GACTTGTACACACAAAGAATTTA CDS 21 1213 8060 OSL162 8044-  8044 TACACACAAAGAATTTACCGAGC CDS 21 1214 8066 OSL163 8150-  8150 ACCAGAAACAACAGTGTAACAAT CDS 21 1215 8172 OSL164 8152-  8152 CAGAAACAACAGTGTAACAATCC CDS 21 1216 8174 OSL165 8167-  8167 AACAATCCTTGTGAACAGTTTAA CDS 21 1217 8189 OSL166 8293-  8293 GTGGACAATGGTGAACGATGTGG CDS 21 1218 8315 OSL167 8564-  8564 CGGAGTTTATGTGCAATAACAGA CDS 21 1219 8586 OSL168 8566-  8566 GAGTTTATGTGCAATAACAGAAG CDS 21 1220 8588 OSL169 8685-  8685 TGGATACACAAAATGTCATAATT CDS 21 1221 8707 OSL170 8689-  8689 TACACAAAATGTCATAATTCAAA CDS 21 1222 8711 OSL171 8691-  8691 CACAAAATGTCATAATTCAAATA CDS 21 1223 8713 OSL172 8699-  8699 GTCATAATTCAAATATTTGTATT CDS 21 1224 8721 OSL173 8715-  8715 TTGTATTCCTCGCGTTTATTTGT CDS 21 1225 8737 OSL174 8768-  8768 GTGATGAAAACCCTACTTATTGC CDS 21 1226 8790 OSL175 8844-  8844 TCCTCAACATTGGTATTGTGATC CDS 21 1227 8866 OSL176 8854-  8854 TGGTATTGTGATCAAGAAACAGA CDS 21 1228 8876 OSL177 8861-  8861 GTGATCAAGAAACAGATTGTTTT CDS 21 1229 8883 OSL178 9063-  9063 TTCCGAGTTTCTCTGTGTAAATG CDS 21 1230 9085 OSL179 9064-  9064 TCCGAGTTTCTCTGTGTAAATGA CDS 21 1231 9086 OSL180 9153-  9153 CGGCTACGATGAGAATCAGAATT CDS 21 1232 9175 OSL181 9181-  9181 AGGAGAACTTGCTCTGAAAATGA CDS 21 1233 9203 OSL182 9221-  9221 GACTGTGTATCCCAAAGATATTC CDS 21 1234 9243 OSL183 9308-  9308 GCCAACAGAATCAGTTTACCTGT CDS 21 1235 9330 OSL184 9595-  9595 GACACCTTAACCAGTTTCTATTG CDS 21 1236 9617 OSL185 9598-  9598 ACCTTAACCAGTTTCTATTGTTC CDS 21 1237 9620 OSL186 9657-  9657 GACTTGTGTTGATATTGATGAAT CDS 21 1238 9679 OSL187 9719-  9719 ATGTAATAGGCTCCTACATCTGT CDS 21 1239 9741 OSL188 9786-  9786 CCGGCAAAACAGTAACATCGAAC CDS 21 1240 9808 OSL189 9807-  9807 ACCCTATCTCATTTTTAGCAACC CDS 21 1241 9829 OSL190 9826-  9826 AACCGTTACTATTTGAGAAATTT CDS 21 1242 9848 OSL191 9827-  9827 ACCGTTACTATTTGAGAAATTTA CDS 21 1243 9849 OSL192 9828-  9828 CCGTTACTATTTGAGAAATTTAA CDS 21 1244 9850 OSL193 9832-  9832 TACTATTTGAGAAATTTAACTAT CDS 21 1245 9854 OSL194 9838-  9838 TTGAGAAATTTAACTATAGATGG CDS 21 1246 9860 OSL195 9849-  9849 AACTATAGATGGCTATTTTTACT CDS 21 1247 9871 OSL196 9892-  9892 GACAATGTTGTGGCATTAGATTT CDS 21 1248 9914 OSL197 9925-  9925 GAGAAGAGATTGTATTGGATTGA CDS 21 1249 9947 OSL198 9956-  9956 GGCAAGTCATTGAGAGAATGTTT CDS 21 1250 9978 OSL199 9987-  9987 GACAAACAAGGAGACAATCATAA CDS 21 1251 10009 OSL200 10272- 10272 AACCAACAAGTCTGTGATAATCT CDS 21 1252 10294 OSL201 10444- 10444 TTCGCTATTACCATTTTTGAAGA CDS 21 1253 10466 OSL202 10446- 10446 CGCTATTACCATTTTTGAAGACA CDS 21 1254 10468 OSL203 10499- 10499 CAGTGGAAAAGGGAAACAAATAT CDS 21 1255 10521 OSL204 10513- 10513 AACAAATATGATGGATCAAATAG CDS 21 1256 10535 OSL205 10574- 10574 TCCATGTGTACCATCCATATAGG CDS 21 1257 10596 OSL206 10958- 10958 CTGATGAAGACCGTCTTCTTTGT CDS 21 1258 10980 OSL207 11246- 11246 GTGACAACTTCACAGAATTCAGC CDS 21 1259 11268 OSL208 11623- 11623 CAGTGTACAAGTGGACATTGTGT CDS 21 1260 11645 OSL209 11625- 11625 GTGTACAAGTGGACATTGTGTAC CDS 21 1261 11647 OSL210 11745- 11745 TACTATGTTCGAATGCAAAAACC CDS 21 1262 11767 OSL211 11749- 11749 ATGTTCGAATGCAAAAACCATGT CDS 21 1263 11771 OSL212 11757- 11757 ATGCAAAAACCATGTTTGTATCC CDS 21 1264 11779 OSL213 11779- 11779 CCGCCATATTGGAAATGTGATGG CDS 21 1265 11801 OSL214 11820- 11820 TGGTTCAGATGAAGAACTTCACC CDS 21 1266 11842 OSL215 11887- 11887 GACAACAATCGCTGCATTTATAG CDS 21 1267 11909 OSL216 11984- 11984 CCCCTAAACCTTGTACAGAATAT CDS 21 1268 12006 OSL217 11985- 11985 CCCTAAACCTTGTACAGAATATG CDS 21 1269 12007 OSL218 11990- 11990 AACCTTGTACAGAATATGAATAT CDS 21 1270 12012 OSL219 11991- 11991 ACCTTGTACAGAATATGAATATA CDS 21 1271 12013 OSL220 11994- 11994 TTGTACAGAATATGAATATAAGT CDS 21 1272 12016 OSL221 12083- 12083 CCGATGAACTGGGTTGCAATAAA CDS 21 1273 12105 OSL222 12114- 12114 AAGAACATGTGCTGAAAATATAT CDS 21 1274 12136 OSL223 12140- 12140 AGCAAAATTGTACCCAATTAAAT CDS 21 1275 12162 OSL224 12193- 12193 GGGTTCGAAACCAATGTTTTTGA CDS 21 1276 12215 OSL225 12197- 12197 TCGAAACCAATGTTTTTGACAGA CDS 21 1277 12219 OSL226 12389- 12389 CTGACAATGTCCGAATTCGAAAA CDS 21 1278 12411 OSL227 12397- 12397 GTCCGAATTCGAAAATATAATCT CDS 21 1279 12419 OSL228 12399- 12399 CCGAATTCGAAAATATAATCTCT CDS 21 1280 12421 OSL229 12435- 12435 CTCAGAGTATCTTCAAGATGAGG CDS 21 1281 12457 OSL230 12443- 12443 ATCTTCAAGATGAGGAATATATC CDS 21 1282 12465 OSL231 12537- 12537 GGGCTCTAGGTTTGGTGCTATCA CDS 25 1283 12561 AA OSL232 12564- 12564 TGCCTACATCCCCAACTTTGAAT CDS 21 1284 12586 OSL233 12608- 12608 AGGAAGTTGACCTGAAACTGAAA CDS 21 1285 12630 OSL234 12616- 12616 GACCTGAAACTGAAATACGTAAT CDS 21 1286 12638 OSL235 12617- 12617 ACCTGAAACTGAAATACGTAATG CDS 21 1287 12639 OSL236 12705- 12705 ACGCATTGAGGTGGCTAAACTTG CDS 21 1288 12727 OSL237 12792- 12792 TCCCAAACTAGGGCTTATGTTCT CDS 21 1289 12814 OSL238 12825- 12825 GGGAAAGGAACCTAAAATCGAGT CDS 21 1290 12847 OSL239 12870- 12870 CCGCAACATCCTGGTTTTCGAGG CDS 21 1291 12892 OSL240 12911- 12911 GCCTTTCTATCGATTATTTGAAC CDS 21 1292 12933 OSL241 12915- 12915 TTCTATCGATTATTTGAACAATG CDS 21 1293 12937 OSL242 12965- 12965 AGGACGTTATTGAAACCATAAAA CDS 21 1294 12987 OSL243 12967- 12967 GACGTTATTGAAACCATAAAATA CDS 21 1295 12989 OSL244 12968- 12968 ACGTTATTGAAACCATAAAATAT CDS 21 1296 12990 OSL245 12995- 12995 GGACTGATAGGAGAGTCATTGCA CDS 21 1297 13019 AA OSL246 13058- 13058 ACCAGTTATACTGGATATCTAAG CDS 25 1298 13080 OSL247 13086- 13086 GGGAGAAGTATGGAAACAAAATA CDS 21 1299 13108 OSL248 13091- 13091 AAGTATGGAAACAAAATAAATTT CDS 21 1300 13113 OSL249 13175- 13175 TTCATCAACTCAGATACAATAAG CDS 21 1301 13197 OSL250 13368- 13368 CGGAGGAAATTGCTATTTTGATG CDS 21 1302 13390 OSL251 13371- 13371 AGGAAATTGCTATTTTGATGAGA CDS 21 1303 13393 OSL252 13428- 13428 CACCGGAAAATATTGTGAAATGG CDS 21 1304 13450 OSL253 13440- 13440 TTGTGAAATGGCGTTTTCAAAAG CDS 21 1305 13462 OSL254 13541- 13541 CAGGATTCTTCCACTATAGAAGG CDS 21 1306 13563 OSL255 13659- 13659 GGCAGATCTTAACATGGATATTG CDS 21 1307 13681 OSL256 13725- 13725 GGCAATGAGTGAAGACTTTGTCA CDS 21 1308 13747 OSL257 13842- 13842 ATCTGAAAATGTGGATAATAAGA CDS 21 1309 13864 OSL258 13844- 13844 CTGAAAATGTGGATAATAAGAAT CDS 21 1310 13866 OSL259 13852- 13852 GTGGATAATAAGAATTATGGAAG CDS 21 1311 13874 OSL260 13853- 13853 TGGATAATAAGAATTATGGAAGT CDS 21 1312 13875 OSL261 13951- 13951 TGGAATCTCTTCAAACGAAAATC CDS 21 1313 13973 OSL262 13955- 13955 ATCTCTTCAAACGAAAATCTAAA CDS 21 1314 13977 OSL263 13957- 13957 CTCTTCAAACGAAAATCTAAACA CDS 21 1315 13979 OSL264 13960- 13960 TTCAAACGAAAATCTAAACAAAC CDS 21 1316 13982 OSL265 13964- 13964 AACGAAAATCTAAACAAACTACC CDS 21 1317 13986 OSL266 13976- 13976 AACAAACTACCAACTTTGAAAAT CDS 21 1318 13998 OSL267 13983- 13983 TACCAACTTTGAAAATCCAATCT CDS 21 1319 14005 OSL268 13987- 13987 AACTTTGAAAATCCAATCTATGC CDS 21 1320 14009 OSL269 14121- 14121 TGCAACAGAAGACACTTTTAAAG CDS 21 1321 14143 OSL270 14145- 14145 CACCGCAAATCTTGTTAAAGAAG CDS 21 1322 14167 OSL271 14148- 14148 CGCAAATCTTGTTAAAGAAGACT CDS 21 1323 14170 OSL272 14169- 14169 CTCTGAAGTATAGCTATACCAGC CDS/ 21 1324 14191 3′- UTR OSL273 14186- 14186 ACCAGCTATTTAGGGAATAATTA 3′-UTR 21 1325 14208 OSL274 14188- 14188 CAGCTATTTAGGGAATAATTAGA 3′-UTR 21 1326 14210 OSL275 14211- 14211 AACACACTTTTGCACATATATTT 3′-UTR 21 1327 14233 OSL276 14213- 14213 CACACTTTTGCACATATATTTTT 3′-UTR 21 1328 14235 OSL277 14236- 14236 TACAAACAGATGAAAAAAGTTAA 3′-UTR 21 1329 14258 OSL278 14252- 14252 AAGTTAACATTCAGTACTTTATG 3′-UTR 21 1330 14274 OSL279 14261- 14261 TTCAGTACTTTATGAAAAAAATA 3′-UTR 21 1331 14283 OSL280 14263- 14263 CAGTACTTTATGAAAAAAATATA 3′-UTR 21 1332 14285 OSL281 14341- 14341 CCGTCTCATATTTTTACAAATAA 3′-UTR 21 1333 14363 OSL282 14355- 14355 TACAAATAATTATCACAATGTAC 3′-UTR 21 1334 14377 OSL283 14366- 14366 ATCACAATGTACTATATGTATAT 3′-UTR 21 1335 14388 OSL284 14368- 14368 CACAATGTACTATATGTATATCT 3′-UTR 21 1336 14390 OSL285 14372- 14372 ATGTACTATATGTATATCTTTGC 3′-UTR 21 1337 14394 OSL286 14396- 14396 CTGAAGTTGTCTGAAGGTAATAC 3′-UTR 21 1338 14418 OSL287 14406- 14406 CTGAAGGTAATACTATAAATATA 3′-UTR 21 1339 14428 OSL288 14437- 14437 TTGTAAATTTTGGAAAGATTATC 3′-UTR 21 1340 14459 OSL289 14447- 14447 TGGAAAGATTATCCTGTTACTGA 3′-UTR 21 1341 14469 OSL290 14451- 14451 AAGATTATCCTGTTACTGAATTT 3′-UTR 21 1342 14473 OSL291 14457- 14457 ATCCTGTTACTGAATTTGCTAAT 3′-UTR 21 1343 14479 OSL292 14458- 14458 TCCTGTTACTGAATTTGCTAATA 3′-UTR 21 1344 14480 OSL293 14464- 14464 TACTGAATTTGCTAATAAAGATG 3′-UTR 21 1345 14486 OSL294 14503- 14503 GTGATCATTATAGTAAATGATCC 3′-UTR 21 1346 14525 OSL295 14513- 14513 TAGTAAATGATCCAACAAGAAAA 3′-UTR 21 1347 14535 OSL296 14523- 14523 TCCAACAAGAAAAGGAATTGACT 3′-UTR 21 1348 14545 OSL297 14579- 14579 CACTCATATTTCCTATAAAATTA 3′-UTR 21 1349 14601 OSL298 14581- 14581 CTCATATTTCCTATAAAATTATC 3′-UTR 21 1350 14603 OSL299 14633- 14633 GTCCATTTTTACACATTAGCACT 3′-UTR 21 1351 14655 OSL300 14649- 14649 TAGCACTTAATTAATGTTCAATA 3′-UTR 21 1352 14671 OSL301 14650- 14650 AGCACTTAATTAATGTTCAATAT 3′-UTR 21 1353 14672 OSL302 14652- 14652 CACTTAATTAATGTTCAATATTA 3′-UTR 21 1354 14674 OSL303 14665- 14665 TTCAATATTACATGTCAATTTGA 3′-UTR 21 1355 14687 OSL304 14684- 14684 TTGATTAATGGCTATGTTGATAG 3′-UTR 21 1356 14706 OSL305 14708- 14708 GGCCACTATGTGTTGTATAGACA 3′-UTR 21 1357 14730 OSL306 14711- 14711 CACTATGTGTTGTATAGACATCT 3′-UTR 21 1358 14733 OSL307 14767- 14767 AGGTAGGAAAAGCAATTCAGTTT 3′-UTR 21 1359 14789 OSL308 14856- 14856 GCCAAGACAACATTTTTATTTGT 3′-UTR 21 1360 14878 OSL309 14861- 14861 GACAACATTTTTATTTGTGATGT 3′-UTR 21 1361 14883 OSL310 14886- 14886 ATGAGGAAATCCCATATCATTAA 3′-UTR 21 1362 14908 OSL311 14921- 14921 TGCATTGAGTTTGTGGTTAATTA 3′-UTR 21 1363 14943 OSL312 14925- 14925 TTGAGTTTGTGGTTAATTAAATG 3′-UTR 21 1364 14947 OSL313 15034- 15034 AGCTGAATTTCTGAAACCAAATC 3′-UTR 21 1365 15056 OSL314 15049- 15049 ACCAAATCTGTGTCTTCATAAAA 3′-UTR 21 1366 15071 OSL315 15115- 15115 TGGGTTTTTGTTTCTATGAAAAT 3′-UTR 21 1367 15137 OSL316 15122- 15122 TTGTTTCTATGAAAATATCATTA 3′-UTR 21 1368 15144 OSL317 15126- 15126 TTCTATGAAAATATCATTATAAT 3′-UTR 21 1369 15148 OSL318 15130- 15130 ATGAAAATATCATTATAATCACT 3′-UTR 21 1370 15152 OSL319 15138- 15138 ATCATTATAATCACTATTTATTT 3′-UTR 21 1371 15160 OSL320 15188- 15188 AACCATTCTTATTAAGCTTTTTA 3′-UTR 21 1372 15210 OSL321 15189- 15189 ACCATTCTTATTAAGCTTTTTAT 3′-UTR 21 1373 15211 OSL322 15220- 15220 GTGGCTAAATGTGTACATTTATA 3′-UTR 21 1374 15242 OSL323 15221- 15221 TGGCTAAATGTGTACATTTATAT 3′-UTR 21 1375 15243 OSL324 15222- 15222 GGCTAAATGTGTACATTTATATT 3′-UTR 21 1376 15244 OSL325 15228- 15228 ATGTGTACATTTATATTAGAATG 3′-UTR 21 1377 15250 OSL326 15263- 15263 CAGATCTTTTCTTTAATTCTTAT 3′-UTR 21 1378 15285 OSL327 15266- 15266 ATCTTTTCTTTAATTCTTATTGG 3′-UTR 21 1379 15288 OSL328 15271- 15271 TTCTTTAATTCTTATTGGTTTTT 3′-UTR 21 1380 15293 OSL329 15438- 15438 CTCTTAAATAGTGGGTATAGTCT 3′-UTR 21 1381 15460 OSL330 15524- 15524 GTGCTAATATTGCACATTTGTTA 3′-UTR 21 1382 15546 OSL331 15525- 15525 TGCTAATATTGCACATTTGTTAA 3′-UTR 21 1383 15547 OSL332 15575- 15575 ATGGATGAATGAATGAAACATAT 3′-UTR 21 1384 15597 OSL333 15583- 15583 ATGAATGAAACATATACTACTGA 3′-UTR 21 1385 15605 OSL334 15587- 15587 ATGAAACATATACTACTGATTAT 3′-UTR 21 1386 15609 OSL335 15591- 15591 AACATATACTACTGATTATTTTA 3′-UTR 21 1387 15613 OSL336 15655- 15655 CTGACTGTAATTACTTTGATTAG 3′-UTR 21 1388 15677 OSL337 15659- 15659 CTGTAATTACTTTGATTAGATAA 3′-UTR 21 1389 15681 OSL338 15675- 15675 TAGATAAACAACTGGAAATAATG 3′-UTR 21 1390 15697 OSL339 15698- 15698 CTGCTGAAAAAGTTCTAATAAAT 3′-UTR 21 1391 15720 OSL340 15699- 15699 TGCTGAAAAAGTTCTAATAAATG 3′-UTR 21 1392 15721

TABLE 11 Additional table of siRNA sequences SEQ SEQ ID ID OSID antisense sequence (5′ to 3′) OSID sense sequence (3′ to 5′) NOS: 957 OSC17C-1 CAGUUGCGCAGUUUCUUGUC OSC17B-1 [dT][dT]GUCAACGCGUCA 973 AGUUC[dT][dT] AAGAACAGUCAAG 958 OSC17C-2 CAGUUGCGCAGUUUCUUGU OSC17B-2 [dT][dT]*G*UCAACGCGUC 974 [mC][mA]GUUC[dT][dT] AAAGAACAGUCAAG 959 OSC17C-3 CAGUUGCGCAGUUUCU[mU] OSC17B-3 [dT][dT]*G*UCAACGCGUC 975 [mG]UCAGUUC[dT][dT] AAAGAACAG[mU]CAAG 960 OSC17C-4 CAGUUGCGCAGUUUCU[mU] OSC17B-4 [dT][dT]*G*UCAACGCGUC 976 [mG]U[mC][mA]GUUC[dT][dT] AAAGAA[mC]AGUCAAG OSC17B-5 [dT][dT]*G*UCAACGCGUC 977 AAAGAA[mC]AG[mU]CAA G OSC17B-6 [dT][dT]*G*UCAA[mC]GCG 978 UCAAAGAA[mC]AG[mU]C AAG 961 OSC47C-1 AAGAGCUCAGGUCUCUGAGG OSC47B-1 [dT][dT]UUCUCGAGUCCA 979 G[dT][dT] GAGACUCCC 962 OSC47C-2 AAGAGCUCAGGUCUC[mU]GA OSC47B-2 [dT][dT]*U*UCUCGAGUCC 980 GGG[dT][dT] AGAGACUCCC 963 OSC47C-3 AAGAGCUCAGGUCUC[mU][mG] OSC47B-3 [dT][dT]*U*UCUCGAGUCC 981 AGGG[dT][dT] AGAGA[mC]UCCC OSC47B-4 [dT][dT]*U*UCUCGAGUCC 982 AGAG[mA][mC]UCCC OSC47B-5 [dT][dT]*U*UCUCGAG[mU] 983 CCAGAG[mA][mC]UCCC 964 OSL231C-1 UUUGAUAGCACCAAACCUAGA OSL231B-1 [dT][dT]AAACUAUCGUGG 984 GCCC[dT][dT] UUUGGAUCUCGGG 965 OSL231C-2 UUUGA[mU]AG[mC]ACCAAACC OSL231B-2 [dT][dT]*A*AACUAUCGUG 985 [mU]AGAGCCC[dT][dT] GUUUGGAUCUCGGG 966 OSL231C-3 UUUGAUAGCACCAAACC[mU] OSL231B-3 [dT][dT]*A*AACUA[mU]CG 986 [mA]GAGCCC[dT][dT] [mU]9 GGUUUGGA[mU]CUC GGG 967 OSL231C-4 UUUGAUAG[mC]ACCAAACC OSL231B-4 [dT][dT]*A*AACU[mA][mU] 987 [mU]AGAGCCC[dT][dT] C[mG][mU]GGUUUGG[mA] [mU]CUCGGG 968 OSL231C-5 UUUGAUAGCACCAAACC[mU]A OSL231B-5 [dT][dT]*A*AACUGUCGUG 988 GAGCCC[dT][dT] GUUUGGA[mU]CUCGGG OSL231B-6 [dT][dT]*A*AACUGUCG 989 [mU]GGUUUGGA[mU]CUCG GG OSL231B-7 [dT][dT]*A*AACUAUCGUG 990 G[mU]UUGGAUCUCGGG 969 OSL245C-1 UUUGCAAUGACUCUCCUAUCA OSL245B-1 [dT][dT]AAACGUUACUGA 991 GUCC[dT][dT] GAGGAUAGUCAGG 970 OSL245C-2 UUUGCAA[mU][mG]ACUCUCC OSL245B-2 [dT][dT]*A*AACG[mU]UA 992 [mU][mA]UCAGUCC[dT][dT] [mC]UGAGAGGA[mU]AGUC AGG 971 OSL245C-3 UUUGCAAUGACUCUCC[mU] OSL245B-3 [dT][dT]*A*AACGUUACUG 993 [mA]UCAGUCC[dT][dT] AGAGGA[mU]AGUCAGG 972 OSL245C-4 UUUGCAA[mU][mG]ACUCUCCU OSL245B-4 [dT][dT]*A*AACGUUA[mC] 994 AUCAGUCC[dT][dT] UGAGAGGA[mU]AGUCAG G OSL245B-5 [dT][dT]*A*AACGUUACUG 995 AGAGGAUAGUCAGG Key to modifications [dT] = DNA base (T) within RNA oligo [mA], [mG], [mC], [mU] = 2′O-Methyl RNA * = Phosphorothioate linkages

In one embodiment, an RNAi (e.g., a dsRNA) featured herein includes a first sequence of a dsRNA that is selected from the group including the sense sequences of any table herein and a second sequence that is selected from the group consisting of the corresponding antisense sequences of any table herein. A corresponding antisense sequence is a nucleotide sequence within the OSID family for example OSC17. In those instances when we refer to an siRNA with no suffix (e.g., OSC17), we mean that to indicate the dsRNA comprised of the antisense and sense strands corresponding to that number (e.g., OSC17A paired with OSC17S or OSC17C-(n) paired with OSC17B-(n) where “n” is any number of the OSC17 family).

Unless otherwise specified, the compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation. It is understood that the phosphorothioate group, designated by an asterisk (*), constitutes a stereogenic center, and the presence of each such group in a sequence engenders two diastereoisomers. The number of such diastereoisomers in a double stranded RNAi agent may be calculated by the formula 2{circumflex over ( )}n, wherein n represents the number of phosphorothioate groups in a sequence comprised of a double stranded siRNA.

In some embodiments, the antisense strand (identified with “A” in the OS ID name) and/or the sense strand (identified with “S” in the OS ID name) of an RNAi agent comprises or consists of a nucleobase sequence, for example, “OSC17A-1” CAGUUGCGCAGUUUCUUGUCAGUUC[dT][dT] (SEQ ID NO: 17), and the nucleobase sequence may include at least one or more nucleotides as a modified nucleotide, and wherein SEQ ID NO: 17 is located at positions 1 to 25 (5′→3′) of the antisense strand and forms a duplex with the corresponding sense strand (identified as OSC17S-1. In some embodiments, the antisense strand of an RNAi agent comprises or consists of a nucleobase sequence for example CAGUUGCGCAGUUUCUUGUCAGUUC[dT][dT] (SEQ ID NO: 17), wherein all or substantially all or 1, 2, 3, 4 or 5 of the nucleotides are modified nucleotides (see for example SEQ ID NO. 24), and wherein SEQ ID NO: 24 is located at positions 1 to 27 (5′→3′) of the antisense strand. For any antisense or sense strand disclosed herein, in some embodiments, the antisense strand of an RNAi agent comprises or consists of the sequence (5′→3′) wherein * is a phosphorothioate linkage between deoxy thymine [dT]; and/or wherein mC, mA, mG, mU are 2′-O-methyl cytidine, 2′-O-methyl adenine, 2′-O-methyl guanosine, 2′-O-methyl uridine respectively; and/or wherein 2fA, 2fU, 2fG, 2fC are 2′-fluoro adenine, 2′-fluoro uridine, 2′-fluoro guanosine, and 2′-fluoro cytosine respectively. The antisense target on the mRNA is identified with the same name but without the notation of “A” or “S” after the name. An antisense sequence with the same name, for example OSC17A-1 through OSC17A-18 binds to the same nucleotide target sequence.

Sequences shown in Table 4 were transfected into HEK 293 (human embryonic kidney) and MDA-MB-435S (human melanoma) cell lines to determine their ability to reduce the protein expression of LRP2 and CD320 gene/protein. These two cell lines were chosen because of their relatively high expression levels of LRP2 as noted in the Human Protein Atlas at world wide web.proteinatlas.org and the NCI-60 gene expression profiles at discover.nci.nih.gov/cellminer/ so that a change in protein expression for LRP2 was easy to detect.

Referring now to FIGS. 3A-B and FIGS. 3D-E, HEK293 and MDA-MB-231 cells were transfected with 20 nM of indicated siRNAs and incubated for 48 hours. Whole cell lysates were prepared and immunoblotted for CD320 and LRP2 protein levels. The protein levels were normalized to a housekeeping control gene unaffected by the siRNA transfection. The graphs represent the fold change of protein levels compared to the scrambled siRNA control (OSS1). (Average −/+ SEM is shown, n=3).

CD320 and LRP2 protein levels were determined by western blot and quantified by Image Studio Software (LiCor Company), relative to a control protein that is not affected by CD320 or LRP2 knockdown. To determine the efficacy of knockdown, protein levels of CD320 (FIGS. 3 A-B) and LRP2 (FIGS. 3 D-E) on the samples that were exposed to siRNA sequences against the mRNA of either gene, were compared to that in the untreated and scrambled controls (black and gray bars, respectively, in all graphs of FIG. 3 ). We found that both siRNA sequences directed against CD320 (OSC17 and OSC47) almost completely abrogated CD320 expression (circles in FIGS. 3 A-B). siLRP2 sequences resulted in variable efficiency in reducing LRP2 protein. Two sequences (05L231 and OSL245) consistently reduced LRP2 levels 75% or more in both cell lines (circles FIGS. 3 B, E).

Referring now to FIG. 6 , lysates were made from transformed (HEK293) and representative cancer cell lines, and western blot was performed to determine LRP2 protein levels. The cancer cells screened have low levels of LRP2 expression. The results represent the averages +SEM of three independent lysates. The data suggests that the cancer cells screened have very low levels of LRP2 expression.

We transfected a panel of LRP2 and CD320 siRNAs into cancer cell lines derived from multiple tissues and analyzed the levels of LRP2 protein and CD320 protein in the cell line. Representative cell lines from prostate, breast and glioblastoma, and normal fibroblasts were exposed to CD320 and LRP2 siRNAs in an experimental set-up similar to that described for HEK293 and MDA-MB-435S cells. The results are shown in FIGS. 3 C, F, and FIG. 4 .

Referring now to FIGS. 3 C, F; and FIG. 4 , MDA-MB-231 LnCAP, MCF-7 and U251 cells were exposed to siRNA sequences to knockdown CD320 (FIG. 3C, and FIGS. 4 A-C) and LRP2 (FIG. 3 F, and FIGS. 4 D-F), in a similar fashion as described for the data represented in FIGS. 3 A, B, D, and E. CD320 protein knockdown FIG. 3C, and FIGS. 4 A-C, compared to the untreated or scrambled controls, is more than 90% for all cell lines tested. LRP2 knockdown is accomplished in all cell lines too. However, the level of knockdown is less in the LnCAP cells compared to the other cell lines and the sequences that are effective may differ as well (FIG. 3 F, and FIGS. 4 D-F).

Referring now to FIG. 5 , an experimental set up similar to that described in FIG. 3 was employed. Additional prostate and brain cancer cell lines, as well as normal fibroblast, were exposed to siRNAs directed against CD320. Levels of CD320 were nearly abrogated in DU-145 (prostate) cells, whereas the levels of knockdown in A172 brain cells and normal fibroblasts were 21%-33% and 25%-28%, respectively (FIGS. 5 A-C).

From these studies we can conclude that two siRNAs to CD320 (OSC17 and OSC47) are very effective in knocking down CD320 protein levels (80% or more), in nearly every cell line tested. While LRP2 is theoretically harder to knock down because of its size, we have identified two siRNAs, OSL231 and OSL245, that consistently knock down LRP2 in most cell lines in which we can detect LRP2.

In addition, LRP2 protein expression levels are very high in HEK 293 cells and easily detectable by western blot. Cancer cell lines have much lower expression of LRP2 compared to HEK293 cells as measured by western blot (FIG. 6 ), and some cell lines may contain LRP2 at levels below reliable detection.

Referring now to FIG. 7 , the effects of doxorubicin treatment on cell viability, as measured by the CTG assay, are illustrated. A172 and HCC15 cells were plated at 1200 cells/well in a 96 well plate. The next day, cells were treated with doxorubicin at the indicated concentrations. Four days after the doxorubicin exposure was initiated, the cells were assayed for viability using the CTG assay. The line indicates the non-linear fitting of the data to calculate an IC₅₀ value. Instead of visually assessing the effect of CD320/LRP2 gene expression knockdown on cell proliferation (as shown for shRNA-mediated CD320/LRP2 knockdown in FIG. 2 ), a functional assay for quantitating the effect on cell viability of the simultaneous knockdown of LRP2 and CD320 by siRNA was developed. A widely used assay for the measurement of cell viability is the Promega Cell-titer GLO® platform (CTG), which quantifies ATP levels in the cell (live cells produce ATP, dead cells do not). After incubating the cells with the CTG reagent, ATP levels can be indirectly measured as light production using the TECAN luminescence plate reader. As a first step, toxicity of a known chemotherapeutic drug, doxorubicin, was assayed on the cell lines of interest. Doxorubicin was used as a positive control for cell toxicity in our assay. Representative data from A172 brain cancer cells (FIG. 7A) and HCC15 lung cancer cells (FIG. 7B) exposed to doxorubicin are shown in FIG. 7 . From this data, the IC₅₀ of doxorubicin treatment on these cell lines was determined: 132 nm for A172 cells and 167 nm for HCC15 cells. Based upon these findings, a larger screen was initiated to determine the IC₅₀ of doxorubicin in several cancer and non-cancer cell lines, to determine the doxorubicin dose to use when cell lines are used in the viability assay to test the simultaneous knockdown of CD320 and LRP2. The results of the cell lines tested are summarized in Table 8 IC₅₀ determination of doxorubicin.

To quantify the effects of knocking down CD320 and LRP2 on cell proliferation, cells are plated in a 24-well plate. The next day, the cells are transfected with siRNAs to CD320 and/or LRP2. The cell lines may require repeated transfections and/or time for efficient toxicity (cell line dependent). In this experimental set-up there is room for repeat infection should some cell lines require that for efficient toxicity. At the end of the study, the cell lines are analyzed for cell growth by the CTG assay. A schematic of this experimental setup is presented in FIG. 8 .

TABLE 8 Cancer type Cell line IC₅₀ (nM) Glioblastoma A172 132 U251 24 Breast MDA-MB-231 43 MCF7 121 Prostate DU145 248 PC3 387 Lung NCI-H460 56 A549 126 HCC15 167 Melanoma MDA-MB-435S 325 Other GM05659 267 HEK293 29

The cells lines were plated at 1,000 to 4,000 cells/well in a 96-well plate and treated with doxorubicin the following day. CTG activity was measured 4 days after treatment. IC₅₀ values were calculated by GraphPad Prism Software. Results are tabulated in Table 8.

These data show that doxorubicin works efficiently on this CTG platform (i.e., doxorubicin kills cancer cells) and can thus be used as a positive control in the in vitro assay to compare the cytotoxic effects of siRNA-knockdown of CD320 and LRP2. In this latter assay, normal or cancer cells are transfected with individual or combinations of siRNAs sequences that are targeting CD320 or LRP2 specifically or control siRNAs, similar to the experiments that provided the data for FIGS. 3, 4, and 5 . In FIGS. 3, 4, and 5 , protein levels are measured, but in the in vitro assay, cell viability is measured.

Referring now to FIG. 8 , an overview of a functional assay for screening (ds) siRNA effects on cell proliferation is illustrated. To quantify the effects of knocking down CD320 and LRP2 on cell proliferation, cells are plated in a 24-well plate. The next day, the cells are transfected with siRNAs to CD320 and/or LRP2. The cell lines may require repeated transfections and/or time for efficient toxicity (cell line dependent). In this experimental set-up there is room for repeat infection should some cell lines require that for efficient toxicity. At the end of the study, the cell lines were analyzed for cell growth by the CTG assay.

Now, referring to FIG. 10B, MDA-MB-231 triple negative breast cancer cells were plated in a 24-well plate at 20,000 cells/well. Cells were transfected the next day with an siRNA selected from the group of OSC17, OSC47, OSL231, and OSL245 at 20 nM. Cells were also transfected with combinations of two siRNAs each of 10 nM, one of these targeting CD320 and the other LRP2, with the siRNAs targeting CD320 selected from the group of OSC17 and OSC47, and the LRP2 targeting siRNAs selected from the group of OSL231 and OSL245, each dosed at 10 nM. Cells were repeated transfected 4 times over the course of 11 days as indicated in Table 9. At day 11, cells were analyzed for cell growth by the CTG assay. The percent cell survival compared to the non-targeting control (OSS2) is shown. The data represented is the average of 6 experiments −/+ SEM.

Now, referring to FIG. 11 , MDA-MB-231 and DU-145 cells were transfected with 20 nM of the negative control siRNA (OSS2), 20 nM siRNA targeting CD320 (OSC17), or 20 nM siRNA targeting LRP2 (05L245). Cells were also transfected with a combination of a CD320 targeting siRNA (OSC17) and LRP2 targeting siRNA (05L24), over a range of concentrations (2-20 nM), so the concentration of the two siRNAs equaled 20 nM total siRNA transfected, as indicated in FIG. 11 . Cells were repeatedly transfected as indicated in Table 9, and the percent cell survival is shown.

Now, referring to FIG. 12 , MDA-MB-231 breast cancer cells were transfected with 20 nM of the negative control siRNA (OSS2), 20 nM siRNA targeting CD320 (OSC17), or 20 nM siRNA targeting LRP2 (05L245). Each day, over five days, lysates were prepared. Western blotting was performed on the lysates for CD320 protein levels (FIG. 12A) or LRP2 protein levels (FIG. 12B).

Referring now to FIG. 9 and FIG. 10 , data quantifying the effects of knocking down CD320 and LRP2 in various cell lines is represented. Cell lines representative of several types of cancers or normal fibroblasts were transfected with individual or combinations of siRNAs to CD320 or LRP2 as indicated. Cells were repeatedly transfected as outlined in Table 9 for efficient toxicity, then assayed for viability by the CTG assay. Doxorubicin treated cells served as a positive control for cell toxicity in our assays.

The data of the individual experiments presented in FIG. 9 and FIG. 10 and additional cell lines we have screened are summarized in Table 9. These experiments show the broad applicability of siCD320 and siLRP2 toxicity in a variety of cancer types.

Referring now to FIG. 13 , a schematic of PEI and siRNA complexes is illustrated. PEI and siRNAs are mixed together. Subsequently, polyplexes (a nanoparticle, broadly speaking) form of the PEI-siRNA complex, which are able to enter the cell via an endocytotic or pinocytotic mechanism.

Referring now to FIG. 14 , siRNAs are short RNA duplexes of generally 16 to 30 nucleotides; the sequence of the siRNA is complementary to a mRNA expressed in the cell. Exogenous siRNA duplexes are introduced into the cell via a method of transfection. The siRNA duplexes are unwound via the RISC (RNA-induced silencing complex) complex, whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC/AGO complex, which has RNAse cleave activity. The end result is that the mRNA targeted by the siRNA is degraded, and the protein encoded by the mRNA is not produced. This causes the “knockdown” effect or reduced protein levels of the gene targeted by the siRNA compared to control-treated cells.

Referring now to FIG. 15 effectiveness of INTERFERin in delivering siRNAs to cancer cells is illustrated. 2 nM of indicated siRNAs were transfected into A172 and MDA-MB-435S cells as per the manufacturers protocol. Cell lysates were prepared 3 days post-infection and analyzed by western blot for CD320 protein levels. OSS1 and OSS2 are non-targeting siRNA controls. In this experiment, both sequences were tested. CD320 protein levels were knocked down to 9% to 18% for A172 cells and 26% to 48% for MDA-MB-435S cells, compared to OSS1. Much more efficient knockdown of CD320 is observed when the siRNAs were delivered with other transfection reagents (e.g. RNAiMAX, Viromer Blue) that were used in the experiments described previously particularly for MDA-MB-435S cells. The Polyplus INTERFERin platform has been tested in vitro in our laboratory in a proof of principle experiment, whereby the platform is able to deliver siRNAs to the target cells in vitro.

Referring now to FIG. 16 , treatment of breast, prostate, and skin cancer cells with an inhibitor of CD320 receptor or an inhibitor of LRP2 receptor or a combination of both in an amount effective to inhibit proliferation of the cancer cells as compared to the control cells treated with control siRNA is illustrated. MDA-MB-231, DU145, LnCAP, and MDA-MB-435S cells were plated at 20,000 cells per well in a 24-well plate. The next day, the cells were transected with 20 nM of indicated siRNAs to knock down CD320, LRP2, or scrambled control. For the combination of siRNAs, cells were treated with 10 nM of each siRNA for 20 nM total treatments. Cells were repeatedly transfected as in Table 9 for the length of time indicated in Table 9. The indicated pictures of the cells were taken at the end of the experiment.

TABLE 9 Summary of functional siRNA data screening Single siRNA knockdown Double siRNA knockdown (siCD320) (siLRP2) OSC17+ OSC47+ # of Days OSC- OSO- OSL- OSL- OSL OSL OSL OSL Cell line n txns expt 17 47 231 245 231 245 231 245 DOX Normal GM05659 3 4 7 133 104 96 103 111 129 97 107 39 Lung HCC15 3 2 7 86 109 68 92 81 93 38 105 2 H157 3 5 8 7 9 116 33 119 39 31 15 20 Melanoma MDA-MB-435S 4 5 10 119 108 92 31 122 56 103 70 51 Prostate LnCAP 3 4 7 52 42 72 60 68 51 52 57 38 DU-145 6 4 7 39 82 71 44 80 44 90 76 40 Glioblastoma A172 3 5 7 94 17 50 101 73 107 19 51 8 U251 4 6 8 94 50 77 97 99 94 66 87 51 Breast MCF-7 3 2 7 61 69 32 68 31 52 26 48 5 MDA-MB-231 6 4 11 66 81 130 77 71 44 81 61 7 Note: The numbers represent percent survival compared to negative control OSS2.

A murine human tumor xenograft model was established using triple-negative breast cancer cells (MDA-MB-231) injected into the flanks of nude mice to test the efficacy of combined dosing of OSC17 and OSL245. The administration of the drug is by repeated dosing over a range of drug concentrations using intratumoral, iv, ip or specialized route of administration. The dosing schedule is based on pilot studies to determine the tolerability of the delivery vehicle and the drug and will incorporate ranges that are taught in the art. Among the delivery platforms are nanoparticles, liposomes, micelles, polymers, small molecule conjugates, aptamers and antibody conjugates. Hybrid technologies containing elements of the aforementioned delivery systems are also known.

The manufacturing process consists of synthesizing the two single strand oligonucleotides of the duplex by conventional solid phase oligonucleotide synthesis. After purification, the two oligonucleotides are annealed into the duplex.

In vivo JetPEI® is a cationic polymer delivery system that binds the negatively charged siRNA molecules to the cationic polyamine polymer. Its use has been reported in xenograft models using MCF-7 (breast), MDA-MB-231 (breast) and A549 (lung) cell lines both ip and intratumoral. This delivery system is currently used in seven human clinical trials (Table 10). The formulated siRNAs are reported to be very stable.

TABLE 10 Clinical trial use of in vivo-jetPEI ® Organization Type of study Phase Cancer Targeting Systems Imaging and cancer Pre-clinical therapy Benitec Lung metastases Pre-clinical Avena Blood-brain barrier Pre-clinical BiOncoTech Melanoma immunotherapy Phase 1 Ottawa Hospital Research Acute myocardial infarction Phase 1 Institute gene therapy CHU-Toulouse, Rangueil Pancreatic cancer gene Phase 2 Hospital therapy BioCancell Bladder cancer gene Phase 3 therapy

Note that in the specification and claims, “about” or “approximately” means within twenty percent (20%) of the numerical amount cited. Although the invention has been described in detail with particular reference to these embodiments, other embodiments can achieve the same results. For example, antisense oligonucleotides that are complimentary to the target mRNA can inhibit expression of the protein of interest even though the antisense oligonucleotide is not provided as a dsRNA and may not bind to RISC/AGO complex. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover in the appended claims all such modifications and equivalents. The entire disclosures of all references, applications, patents, and publications cited above are hereby incorporated by reference. 

1. A double stranded RNA interference (RNAi) agent comprising: (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a CD320 gene wherein the first dsRNA comprises a sense strand and an antisense strand forming a duplex, (ii) a second dsRNA for inhibiting the expression of a LRP2 gene wherein the second dsRNA comprises a sense strand and an antisense strand forming a duplex, and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA.
 2. The double stranded RNAi agent of claim 1 wherein the antisense strand of (i) the first dsRNA includes a region of complementarity to a CD320 RNA transcript.
 3. The double stranded RNAi agent of claim 1 wherein the sense strand of (i) the first dsRNA is selected from Table
 5. 4-6. (canceled)
 7. The double stranded RNAi agent of claim 1 wherein the antisense strand of (i) the first dsRNA, comprises the nucleotide sequence selected from (5′→3′) (SEQ ID NO: 17) CAGUUGCGCAGUUUCUUGUCAGUUCdTdT; (SEQ ID NO 18) CAGUUGCGCAGUUUCUUGUCAGUUCdT*dT; (SEQ ID NO 19) mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmUmGmUmCmAmGmUmUmCd T*dT; (SEQ ID NO 21) mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmUmGmUmCmAmGmUmUmC; (SEQ ID NO 23) mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmUmGmUmCmAmGmUmUmCd T*dT; (SEQ ID NO 24) mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCm A2fGmU2fUmCdT*dT; (SEQ ID NO 25) mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCm A2fGmU2fUmC; (SEQ ID NO 28) 2fCmA2fGmU2fUmG2fCmG2fCmA2fGmU2fUmU2fCmU2fUmG2fUmC2 fAmG2fUmU2fCdT*dT; (SEQ ID NO 29) 2fCmA2fGmU2fUmG2fCmG2fCmA2fGmU2fUmU2fCmU2fUmG2fUmC2 fAmG2fUmU2fC; (SEQ ID NO 30) mC2fA2fG2fU2fU2fG2fC2fG2fC2fA2fG2fU2fU2fU2fC2fU2fU2 fG2fU2fC2fA2fG2fU2fU2fCdT*dT; (SEQ ID NO 32) mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCm A2fGmU2fUmCdT*dT; (SEQ ID NO 33) mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCm A2fGmU; (SEQ ID NO 34) mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fU2fU2fG2fU2f C2fA2fG2fU;

wherein, mA, mC, mG, and mU are 2′-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2′-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.
 8. The double stranded RNAi agent of claim 1 wherein the antisense strand of (i) the first dsRNA, comprises the nucleotide sequence selected from (5′→3′) (SEQ ID NO 64) AAGAGCUCAGGUCUCUGAGGGdTdT; (SEQ ID NO 65) AAGAGCUCAGGUCUCUGAGGGdT*dT; (SEQ ID NO 66) mAmAmGmAmGmCmUmCmAmGmGmUmCmUmCmUmGmAmGmGmGdT*dT; (SEQ ID NO 68) mAmAmGmAmGmCmUmCmAmGmGmUmCmUmCmUmGmAmGmGmG; (SEQ ID NO 71) mA2fAmG2fAmG2fCmU2fCmA2fGmG2fUmC2fUmC2fUmG2fAmG2fGm GdT*dT; (SEQ ID NO 72) mA2fAmG2fAmG2fCmU2fCmA2fGmG2fUmC2fUmC2fUmG2fAmG2fGm G; (SEQ ID NO 75) 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2 fGdT*dT; (SEQ ID NO 76) 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2 fG; (SEQ ID NO 77) mA2fA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2 fG; (SEQ ID NO 78) mA2fA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2 fGdT*dT; (SEQ ID NO 79) 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2 fGdT*dT; (SEQ ID NO 81) 2fAmA2fGmA2fGmC2f1JmC2fAmG2fGmU2fCmU2fC2f1J2fG2fA2f G2fG2fG;

wherein, mA, mC, mG, and mU are 2′-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2′-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.
 9. The double stranded RNAi agent of claim 1 wherein the sense strand of (i) the first dsRNA is no more than 30 nucleotides in length, and the antisense strand of (i) the first dsRNA is no more than 30 nucleotides in length.
 10. The double stranded RNAi agent of claim 1 wherein the antisense strand of (ii) the second dsRNA includes a region of complementarity to an LRP2 RNA transcript.
 11. The double stranded RNAi agent of claim 1 wherein the antisense strand and the sense strand of (ii) the second dsRNA are selected from Table
 6. 12. The double stranded RNAi agent of claim 1, wherein the antisense strand of (ii) the second dsRNA comprises the nucleotide sequence selected from (5′→3′) (SEQ ID NO: 417) UUUGAUAGCACCAAACCUAGAGCCCdTdT; (SEQ ID NO: 418) UUUGAUAGCACCAAACCUAGAGCCCdT*dT; (SEQ ID NO: 419) mUm[mUmGmAmUmAmGmCmAmCmCmAmAmAmCmCmUmAmGmAmGmCmCmCd T*dT; (SEQ ID NO: 421) mUmUmUmGmAmUmAmGmCmAmCmCmAmAmAmCmCmUmAmGmAmGmCmCmC; (SEQ ID NO: 424) mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGm A2fGmC2fCmCdT*dT]; (SEQ ID NO: 425) mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGm A2fGmC2fCmC; (SEQ ID NO: 429) mU2fAmU2fCmA2fAmA2fCmC2fUmC2fGmA2fUmA2fGmC2fAmA2fCm A2fCmC2fGmC; (SEQ ID NO: 430) mU2fU2fU2fG2fA2fU2fA2fG2fC2fA2fC2fC2fA2fA2fA2fC2fC2 fU2fA2fG2fA2fG2fC2fC2fCdT*dT; (SEQ ID NO: 432) mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGm A2fGmC2fCmCdT*dT; (SEQ ID NO: 433) mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGm A2fGmC; and (SEQ ID NO: 434) mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fC2fC2fU2fA2f G2fA2fG2fC

wherein, mA, mC, mG, and mU are 2′-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2′-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.
 13. The double stranded RNAi agent of claim 1, wherein the antisense strand of (ii) the second dsRNA comprises the nucleotide sequence selected from (5′→3′) (SEQ ID NO: 448) UUUGCAAUGACUCUCCUAUCAGUCCdTdT; (SEQ ID NO: 449) UUUGCAAUGACUCUCCUAUCAGUCCdT*dT; (SEQ ID NO: 450) mUmUmUmGmCmAmAmUmGmAmCmUmCmUmCmCmUmAmUmCmAmGmUmCmCd T*dT; (SEQ ID NO: 452) mUmUmUmGmCmAmAmUmGmAmCmUmCmUmCmCmUmAmUmCmAmGmUmCmC; (SEQ ID NO: 455) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCm A2fGmU2fCmCdT*dT; (SEQ ID NO: 456) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCm A2fGmU2fCmC; (SEQ ID NO: 458) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCm A2fCmU2fCmc; (SEQ ID NO: 459) 2fUmU2fUmG2fCmA2fAmU2fGmA2fCmU2fCmU2fCmC2fUmA2fUmC2 fAmG2fUmC2fCdT*dT; (SEQ ID NO: 460) mU2fAmU2fCmC2fUmA2fAmG2fUmC2fAmC2fAmC2fGmU2fUmU2fGm A2fCmU2fGmC; (SEQ ID NO: 461) mU2fU2fU2fG2fC2fA2fA2fU2fG2fA2fC2fU2fC2fU2fC2fC2fU2 fA2fU2fC2fA2fG2fU2fC2fCdT*dT; (SEQ ID NO: 463) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCm A2fGmU2fCmCdT*dT; (SEQ ID NO: 464) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCm A2fGmU; (SEQ ID NO: 465) mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fC2fU2fA2fU2f C2fA2fG2fU

wherein, mA, mC, mG, and mU are 2′-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2′-fluoro adenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.
 14. (canceled)
 15. The double stranded RNAi agent of claim 1 comprises (iii) the combination of (i) the first dsRNA and (ii) the second dsRNA.
 16. The double stranded RNAi agent of claim 15 wherein the antisense strand of (i) the first dsRNA is selected from (SEQ ID NO: 17) CAGUUGCGCAGUUUCUUGUCAGUUCdTdT; (SEQ ID NO 18) CAGUUGCGCAGUUUCUUGUCAGUUCdT*dT; (SEQ ID NO 64) AAGAGCUCAGGUCUCUGAGGGdTdT; and (SEQ ID NO 65) AAGAGCUCAGGUCUCUGAGGGdT*dT;

and the antisense strand of (ii) the second dsRNA is selected from (SEQ ID NO: 417) UUUGAUAGCACCAAACCUAGAGCCCdTdT; (SEQ ID NO: 418) UUUGAUAGCACCAAACCUAGAGCCCdT*dT; (SEQ ID NO: 448) UUUGCAAUGACUCUCCUAUCAGUCCdTdT; and (SEQ ID NO: 449) UUUGCAAUGACUCUCCUAUCAGUCCdT*dT;

wherein * is a phosphorothioate linkage; and the sense strand is at least substantially complementary to the antisense strand.
 17. The double stranded RNAi agent of claim 1 wherein (i) the first dsRNA has the duplex structure of (SEQ ID NOs: 17 and 110) or (SEQ ID NOs: 18 and 111).
 18. The double stranded RNAi agent of claim 1 wherein (ii) the second dsRNA has the duplex structure of (SEQ ID NOs: 417 and 808) or (SEQ ID NOs: 448 and 822).
 19. An isolated cell comprising a double stranded RNAi agent of claim
 1. 20. A pharmaceutical composition for inhibiting expression of a CD320 gene, the pharmaceutical composition comprising a double stranded RNAi agent (i) and (ii) of claim
 1. 21. A pharmaceutical composition for inhibiting expression of an LRP2 gene, the composition comprising a double stranded RNAi agent (i) and (ii) of claim
 1. 22-23. (canceled)
 24. A method for inhibiting proliferation of a cancer cell (CC) comprising contacting of the CC with an inhibitor of CD320 in an amount effective to inhibit proliferation of the CC. 25-41. (canceled)
 42. A method for inhibiting proliferation of a cancer cell (CC) comprising contacting of the CC with an inhibitor of LRP2 in an amount effective in inhibiting proliferation of the CC. 43-58. (canceled)
 59. A method for inhibiting proliferation of a cancer cell (CC) comprising contacting of the CC with a composition comprising an inhibitor of CD320 and an inhibitor of LRP2 in an amount effective to inhibit proliferation of the CC. 